Genetically-Associated Chronic Obstructive Pulmonary Disease Treatment

ABSTRACT

A system for treating a genetically associated chronic obstructive pulmonary disease. The system includes a coil implant, wherein the coil implant is configured to increase tension of a lung having alveolar damage caused by a genetic disorder and thereby improve breathing function of the lung. The system includes a delivery system configured to deliver the coil implant into an airway of the lung, wherein the delivery system comprises a cartridge configured to retain the coil implant in a straight configuration. The coil implant is configured to recover to a non-straight, pre-determined shape upon deployment within the airway the lung of the patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a Continuation of U.S. application Ser. No.15/717,439 filed Sep. 27, 2017 (Allowed); which is a Divisional of U.S.application Ser. No. 14/525,123 filed Oct. 27, 2014 (now U.S. Pat. No.9,801,637); which claims priority to U.S. Provisional Appln No.61/895,979 filed Oct. 25, 2013; the full disclosures which areincorporated herein by reference in their entirety for all purposes.

This application is also generally related to the following co-assignedreferences, each of which is incorporated by reference:

U.S. Pat. No. 8,721,734, filed May 18, 2010, entitled Cross-SectionalModification During Deployment of an Elongate Lung Volume ReductionDevice;

U.S. Pat. No. 8,262,660, filed Jul. 2, 2008, entitled Minimally InvasiveLung Volume Reduction Devices, Methods, and Systems;

PCT Pub. No. WO2007106495, filed Mar. 13, 2007, entitled MinimallyInvasive Lung Volume Reduction Devices, Methods, and Systems;

U.S. Pat. No. 8,157,837, filed Jun. 2, 2006, entitled Minimally InvasiveLung Volume Reduction Device and Method;

U.S. Provisional Patent Application 60/743,471, filed on Mar. 13, 2006;entitled Minimally Invasive Lung Volume Reduction Device and Method;

U.S. Provisional Patent Application 60/884,804, filed Jan. 12, 2007entitled Minimally Invasive Lung Volume Reduction Devices, Methods andSystems;

U.S. Provisional Patent Application 60/885,305, filed Jan. 17, 2007,entitled Minimally Invasive Lung Volume Reduction Devices, Methods andSystems;

U.S. Pat. No. 8,142,455 filed Sep. 12, 2008, entitled Delivery ofMinimally Invasive Lung Volume Reduction Devices;

U.S. Pat. No. 8,157,823, filed Sep. 12, 2008, entitled Improved LungVolume Reduction Devices, Methods and Systems;

U.S. Pat. No. 9,173,669, filed Sep. 11, 2009, entitled Improved and/orLonger Lung Volume Reduction Devices, Methods, and Systems; and

U.S. Pat. No. 8,632,605, filed Sep. 11, 2009, entitled Elongated LungVolume Reduction Devices, Methods, and Systems.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BACKGROUND OF THE INVENTION Field of the Invention

Devices, systems and methods are described for treating lungs. Theexemplary devices, systems and methods may, for example, improve thequality of life and restore lung function for patients suffering fromgenetically caused emphysema. Embodiments of the systems may include animplant and a delivery catheter. The implant may be advanced throughtortuous anatomy and actuated to retain a pre-determined shape andrigidity. Additionally, the implant may comprise a shape-memory materialor spring material, which may be constrained to a first configurationduring delivery through tortuous anatomy and then allowed to return to asecond configuration during deployment. The deployed implant modifiesthe shape of the airways and compresses intact but diseased parenchymato cause volume reduction and thereby tensions the lung parenchyma torestore elastic recoil. Systems and devices are also included thatdeploy and actuate the implantable devices, as well as systems anddevices designed for recapture of the implanted device.

Emphysema is a destructive disease of the lung that primarily causesshortness of breath. In cases of non-genetic (i.e.,lifestyle/environmentally induced) emphysema tissues that support thephysical shape and function of the lungs are destroyed in emphysematouslungs, typically resulting in atelectasis. The destruction of lungtissue around the alveoli creates airspace enlargement as well asdistortion and collapsibility of the small airways, which become unableto hold their functional shape during exhalation (National Institute ofHealth, 2006). There are multiple non-genetic causes of emphysema, withsmoking being the most common.

A rare, genetic cause of emphysema is Alpha-1 antitrypsin deficiency(AATD). Alpha-1 antitrypsin (AAT, also called alpha-1 protease inhibitoror A1P1) is a protease inhibitor that inhibits a wide variety ofproteases, including the human neutrophil elastase (HNE). Unopposed HNEactivity in the lung causes degradation of elastin, an importantcomponent of the connective tissue matrix of the lung, resulting inemphysema. Emphysema in AATD can occur in the absence of cigarettesmoking or other environmental exposures that are traditionallyassociated with elastin degradation. This type of emphysema not onlydiffers in etiology but also differs in the location and extent of lungtissue damage. The lower lobes of the lung are predominantly affected byAATD, rather than the upper lobes, which are most commonly affected inthe general emphysema population (Holme 2009).

AATD is a rare genetic disease, with estimates of overall prevalenceranging from 26,000 to 155,000 total affected individuals in the UnitedStates for example. AATD patients' symptoms, which includebreathlessness, cough, phlegm, wheeze and fatigue, are oftenmisdiagnosed as asthma. Since these individuals have symptoms that areindistinguishable from usual smoker's Chronic Obstructive PulmonaryDisease (COPD), a correct diagnosis of the underlying genetic causerequires a blood test. The incidence of AATD emphysema in the UnitedStates is estimated to be between 620 and 3,636 cases per year.Unfortunately, the number of individuals diagnosed and known to haveAATD in the United States is approximately 5-10% of the estimatedprevalence of the genetic deficiency. Therefore, it is estimated thatfewer than 400 cases of AATD emphysema are diagnosed each year.

Pharmacotherapy for COPD plus AATD-specific augmentation therapiescomprise the standard of care for diagnosed AATD patients, with somebenefit associated with symptom relief. However, there are no currentlyapproved safe and effective treatments for restoration of lung functionleading to improvement in pulmonary function and daily activity.Augmentation therapies, which increase the plasma levels of AAT throughintravenous infusion of AAT purified from human plasma, have beenapproved by the U.S. Food and Drug Administration (FDA) for AATD-relatedemphysema. Some controversy remains about the clinical efficacy ofaugmentation therapy, however, because there have been no long termprospective, randomized studies of augmentation therapy versus placebothat target clinical outcomes in AATD emphysema. Furthermore,augmentation therapies remain expensive, with yearly costs approachingor in excess of $100,000 (2007 dollars, www.AllergyCases.org).

Highly-invasive lung volume reduction surgery (LVRS) is available formanagement of some types of emphysema, but has been shown not to bebeneficial in patients whose emphysema is caused by AATD (Stoller,2007). AATD-associated emphysema is typically in the lower lung fieldsand is panacinar (a diffuse subtype; Holme, 2009), and LVRS has beenshown to be most effective in patients with upper-lobe predominantdisease. Accordingly, LVRS is not an option for AATD patients.

Several minimally invasive investigational therapies exist and aim atimproving quality of life and restoring lung function for patientssuffering from emphysema. However, these therapies patients patientswith non-genetic emphysema with atelectasis as the desired outcome.These potential therapies include mechanical devices and biologicaltreatments. The Zephyr™ device by Emphasys (Redwood City Calif.) and theIBV device device by Spiration (Redmond Wash.) are mechanical one-wayvalve devices. The underlying theory behind these devices is to achieveabsorptive atelectasis by preventing air from entering diseased portionof the lung, while allowing air and mucous to pass through the deviceout of the diseased regions. The Watanabe spigot is another mechanicaldevice that can seek to completely occlude the airway, therebypreventing air from entering and exiting the lung. Collateralventilation (interlobar and intralobar—porous flow paths that preventcomplete occlusion) may prevent atelectasis for such devices. The lackof atelectasis for lung volume reduction can drastically reduce theeffectiveness of such devices. Other mechanical devices include means ofdeploying anchors into airways and physically deforming airways bydrawing the anchors together via cables.

Biological treatments utilize tissue engineering aimed at causingscarring at specific locations. Unfortunately, it can be difficult tocontrol the scarring and to prevent uncontrolled proliferation ofscarring.

SUMMARY OF THE INVENTION

Many embodiments of the invention are related to an implant system thatis suitable for use in the treatment of emphysema associated withalpha-1 antitrypsin deficiency (AATD). The implant system incorporatesimplants, which can be coil-shaped, and a minimally invasive deliverysystem for placement in the lung. The implant system is intended toimprove lung function in patients with AATD-associated emphysema byintroducing the implant into the affected lung tissue, therebycompressing AATD affected/damaged tissue (lung volume reduction) andrestoring elastic recoil to the remaining undamaged lung tissue viaminimally invasive means. Such an implant system can provide emphysemapatients with AATD-associated emphysema a safe and effective alternativeto living a limited life, by helping to improve lung function leading tobetter breathing, better activity and better quality of life.

The implant system can be delivered via a standard bronchoscope and bedesigned specifically to treat patients suffering from emphysema. Theimplant system may be a two part system that includes 1) sterile,biocompatible, permanent implants and 2) a sterile, biocompatible,disposable, single-use (single-patient) delivery system. The deliverysystem includes a guidewire, catheter, cartridge, and forceps.

The implant can be a self-recovering coil composed of passivatednitinol, a biocompatible super-elastic material that has been usedextensively for implantable medical devices. The self-recovering coil isdelivered into the airway in a straight configuration and recovers to anon-straight, pre-determined shape upon deployment. The self-recoveringcoil is intended to compress the most damaged parenchyma and tension thesurrounding tissue, which increases elastic recoil, reduceshyperinflation and redirects air to healthier portions of the lung formore effective ventilation. The self-recovering coil will effectivelyreduce the volume of damaged parenchyma, even in the presence ofcollateral ventilation. Generally, at least one implant is required,however, since this therapy targets local diseased regions of the lung,approximately 10 implants in a lung may be necessary to achieve adequateeffect

The self-recovering coils are available in varying lengths toaccommodate anticipated anatomical variations, ranging from 100 mm to150 mm. The trailing proximal end of the self-recovering coil (mostproximal 10 mm) has a smaller diameter than the rest of the Cself-recovering coil oil to reduce rigidity, lessen pressure of theself-recovering coil on the airway wall, and facilitate recapture, ifnecessary. The distal and proximal ends of the self-recovering coilterminate with a smooth atraumatic ball. The self-recovering coilgeometry termini may be designed to reside in airways with anapproximate inner diameter of ˜2 mm (distally) and ˜6 mm (proximally).

The delivery system is used to safely deliver the self-recovering coils.The guidewire serves as a specialized large and flexible guide for thecatheter, which enables the identification of suitable airways fortreatment and supports the catheter to help guide it to a delivery site.The guidewire also facilitates the selection of the appropriate coillength. The catheter is a plastic tube passed over the guidewire andfunctions as a conduit to deliver the coil from outside the patient tothe targeted treatment area. It also can be used to reposition or removethe coil. The cartridge is a plastic cylinder with a Luer lock tip thatstraightens the coil, couples to the catheter, and aids in the processof loading the coil into the catheter. The forceps couples to theproximal end of the coil and delivers it through the catheter, enablingthe clinician to control the placement and release of the coil in thetarget airway.

Placement of the implant is designed to affect the AATD lung in thefollowing manner: compress diseased tissue and restore tension to thelung to support functioning lung tissue during inhalation andexhalation; limit airflow to diseased tissue and prevent hyperinflation;shift preferential filling and compliance to normal tissue; and openairways to reduce air-flow limitations.

The implant can be removed by reversing the deployment procedure. Theprocedure is designed to be performed using a therapeutic bronchoscopewith a 2.8 mm working channel (which accommodates the delivery system)and fluoroscopy for visualization beyond the viewing range of thebronchoscope.

The present invention generally provides improved medical devices,systems, and methods, particularly for treating one or both lungs of apatient having genetically related chronic obstructive pulmonarydisease. Embodiments of the invention often make use of elongate implantstructures which can be introduced into an airway system to a targetairway axial region. The target axial region may or may not includebranches, and the implants can be deployed within the airway by bendingor allowing the implant to bend so that the implant compresses adjacentlung tissue. Many embodiments may apply lateral bending and/orcompression forces against the lung tissue from within the airways foran extended period of time. Exemplary embodiments may be placed in thelung to increase gas filling resistance in the portion of the lung.Optionally, embodiments may be deployed within the lung to uncollapsepreviously collapsed airways or blood vessels. Embodiments may comprisea spring or shape memory material which is delivered within a catheterin a delivery configuration to the target airway and then released fromthe catheter to return to a deployed configuration within the airway.Exemplary embodiments may have a configuration which provides a morecontrolled transition from the delivery configuration to the deployedconfiguration during the release of the device from the catheter. Insome embodiments, a proximal end of the device may be configured tofacilitate recapture of the device after the device is deployed withinthe lung. This may be beneficial when the device is deployed in a lessthan ideal position or orientation or when the implant is no longerdeemed necessary.

Many embodiments are releated to a method for treating a geneticallyassociated chronic obstructive pulmonary disease. In the method, atleast one implant is advanced into an airway of a lung a patient havingalpha-1 antitrypsin deficiency. The at least one implant then deliveredinto the lung to increase tension of the lung and thereby improvebreathing function of the lung. In many embodiments the geneticallyassociated chronic obstructive pulmonary disease causes uniformlydiseased alveolus within at least a portion of the lung.

Many embodiments are related to a method for treating a geneticallyassociated chronic obstructive pulmonary disease, in which at least oneimplant is advanced into an airway of a lung having intact and uniformlydiseased alveolus within at least a portion of the lung, such as onelower lobe of the lung. The intact and uniformly diseased alveolus iscompressed using the at least one implant to cause improved breathingfunction of the lung. Advancement and delivery of the at least oneimplant can be performed so that the at least one implant locallycompresses an associated at least one region of the uniformly diseasedtissue.

In many embodiments the genetically associated chronic obstructivepulmonary disease causes uniformly diseased alveolus distributedthroughout a first lobe of the lung, which is a lower lobe of the lung,Advancing and the delivering of the at least one implant are performedso that the at least one implant locally compresses a region of a secondlobe of the lung outside the uniformly diseased tissue, such as an upperor middle lobe of the lung.

In many embodiments it is determined that the patient has a chronicobstructive pulmonary disease, wherein a plurality of alternativetherapies are available for treatment of a plurality of alternativetypes of the chronic obstructive pulmonary disease. The chronicobstructive pulmonary disease of the patient comprises alpha-1antitrypsin deficiency is identified from among a plurality ofalternative chronic obstructive pulmonary diseases. Treatment isselected using the at least one implant from among the plurality ofalternative therapies in response to the determination that the chronicobstructive pulmonary disease of the patient comprises alpha-1antitrypsin deficiency.

Many embodiments are related to a method for treating a geneticallyassociated chronic obstructive pulmonary disease in which at least oneimplant is implanted into a lung having alveolar damage caused byalpha-1 antitrypsin deficiency to increase tension of the lung andthereby improve breathing function of the lung. At least oneaugmentation therapy is provided to boost circulating alpha-1antitrypsin plasma levels within the lung and thereby slow or haltprogression of the alveolar damage to the lung.

Many embodiments are related to a system for treating a geneticallyassociated chronic obstructive pulmonary disease. The system includes ameans for increasing tension of a lung having alveolar damage caused byalpha-1 antitrypsin deficiency and thereby improve breathing function ofthe lung. The system may also include a means for delivering the meansfor increasing tension within the lung. The system may also include ameans for diagnosing the alpha-1 antitrypsin deficiency, wherein themeans for diagnosing provides an indication suitable for prompting useof the at least one delivery catheter.

Many embodiments related to a system for treating a geneticallyassociated chronic obstructive pulmonary disease. The system includes atleast one implant device configured to increase tension of a lung havingalveolar damage caused by alpha-1 antitrypsin deficiency. The systemalso includes at least one delivery catheter for delivering the at leastone implant device to the lung.

Many embodiments related to a method for treating a geneticallyassociated chronic obstructive pulmonary disease, in which at least oneimplant is advanced into an airway of a lung having intact and uniformlydiseased alveolus within at least one lower lobe of the lung. However,the lung has non-diseased alveolus within upper lobes of the lung. Theintact and uniformly diseased alveolus is compressed within at least onelower lobe of the lung using the at least one implant to cause improvedbreathing function of the lung.

In many embodiments, the resultant improved breathing function isassociated with reduced air-trapping within the alveolus. The at leastone implant may be a coil-shaped implant that folds at least one airwayof the lung to increase tension. In many embodiments, a plurality ofimplants and/or a plurality of delivery catheters are used. A pluralityof implants may also be used. The coil can have a distal end and aproximal end, and in a straight configuration ranges 100-150 mm from thedistal end to the proximal end.

In many embodiments, a genetic diagnostic test sample delivery system isincluded for transmitting a genetic specimen from the patient to agenetic diagnostic system configured for diagnosing the alpha-1antitrypsin deficiency, and for providing an indication suitable forprompting use of the at least one delivery catheter.

The coil can be configured to have a relaxed configuration thatdecreases the straight configuration length from the distal end to theproximal end. The uniformly diseased alveolus can be caused by alpha-1antitrypsin deficiency. Compressing the uniformly diseased alveoluscomprises positioning the at least one implant within the lung toincrease tension at the at least one lobe.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the features and advantages of the presentinvention will be obtained by reference to the attached documents thatset forth illustrative embodiments, in which the principles of theinvention are utilized, and the accompanying drawings of which:

FIGS. 1A-1C illustrates the anatomy of the respiratory system;

FIGS. 2A-2D illustrate a bronchoscope;

FIG. 3 illustrates a bronchoscope in combination with a delivery devicefor a lung volume reduction device according to the invention;

FIGS. 4A-4F illustrate a lung volume reduction device according to anaspect of the invention;

FIGS. 5A-5D illustrate a lung volume reduction device according toanother aspect of the invention;

FIG. 6 illustrates a lung volume reduction device according to anotheraspect of the invention;

FIG. 7 illustrates a lung volume reduction device encased in a sheath;

FIGS. 8A-D illustrate a lung volume reduction device according toanother aspect of the invention;

FIGS. 9A-9B illustrate segments suitable for use in configuring a lungvolume reduction device according to an aspect of the invention;

FIG. 10 illustrates an exemplary device in a pre-deployed conditionaccording to aspects of the invention;

FIGS. 11A-11B illustrate a lung volume reduction device according toanother aspect of the invention;

FIGS. 12A-C illustrate a variety of device configurations withatraumatic tips;

FIGS. 13A-13F illustrate a plurality of individual wires formed of shapememory material that can be deployed to form a lung volume reductiondevice and a delivery device;

FIG. 14 illustrates a device configuration;

FIG. 15 illustrates a device in a loading cartridge;

FIG. 16 illustrates a long device configuration;

FIG. 17 illustrates a device configuration with a wire support frame;

FIG. 18 illustrates a device configuration with a covering;

FIG. 19 illustrates a device configuration with a perforated covering;

FIG. 20 illustrates a device configuration with an attached wire supportframe;

FIG. 21 illustrates a device configuration with an attached frame andcovering;

FIG. 22 illustrates a device configuration that is coupled to a seconddevice;

FIG. 23 illustrates a device configuration in a coil shape;

FIGS. 24A-E illustrate a device with two helical sections and atransition section;

FIGS. 25A-D illustrate the device of FIGS. 24A-E further comprising ajacket;

FIGS. 26A-E illustrate another embodiment of the device with two helicalsections and a transition section;

FIGS. 27A-D illustrate the device of FIGS. 26A-E further comprising ajacket;

FIG. 28 illustrates a device in a delivery configuration during deliverywithin an airway;

FIG. 29 illustrates the device of FIG. 28 deployed to the deployedconfiguration within the airway;

FIGS. 30 and 31 are images of human lung tissue before and after aportion of the lung tissue is compressed from within an airway by anembodiment of an implant;

FIGS. 32A-32C illustrate a device implanted within the lungs;

FIG. 33A illustrates a method steps for implanting the device;

FIG. 33B illustrates a method steps for implanting the device;

FIG. 34 illustrates a system in an airway with device ready to deliver;

FIG. 35 illustrates a system in an airway delivering the device;

FIG. 36 illustrates a system in an airway with the device delivered;

FIG. 37 illustrates a system with a bronchoscope, catheter, dilator, andguidewire;

FIGS. 38A-38B illustrate the delivery of the device;

FIG. 39 schematically illustrates selection from among a plurality ofalternative devices with different lengths, and loading of a device intoa cartridge so that the device can be advanced into a delivery catheter;and

FIGS. 40A-40C illustrate the delivery of a lung volume reduction deviceaccording to embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION I. Etiology and Description ofAATD

Alpha-1 antitrypsin deficiency was first reported in 1963 by Carl-BertilLaurell and Sten Eriksson. They observed a link between low plasma serumlevels of alpha-1-antitrypsin and symptoms of pulmonary emphysema.

Alpha-1 antitrypsin is a 52 kD protein belonging to the serpin family ofprotease inhibitors. Though AAT inhibits multiple targets, it is nowknown that a major target of inhibition is the human neutrophil elastase(HNE) (Sandhaus, 2004). HNE, in the absence of adequate inhibition byAAT, is free to break down elastin, which creates a loss of theelasticity in the lung tissue, resulting in respiratory complicationssuch as emphysema.

The molecular structure of AAT includes 394 amino acids with 3glycosylated side-chains. The AAT active site has a methionine moleculethat is susceptible to conversion to methionine sulfoxide by oxidantsfrom cigarette smoke, greatly reducing AAT's inhibitory activity on HNE.Thus, low serum levels of AAT can contribute to early onset of clinicalsymptoms (Russi 2008; ATSERS, 2003).

AATD results when there is a mutation in the gene that directs the bodyto make the AAT protein. This SERPINA1 gene is carried by both males andfemales and thus can be inherited from either parent. Genetic AATD isassociated with inheritance of one or two alleles with reduced AATexpression or activity (Kumar, 2005). Thus, levels of circulating alpha1-antitrypsin in the blood depend on genotype. The most common

AAT alleles are:

-   -   M—Normal (associated with normal amounts of AAT protein)    -   S (slightly deficient) and Z (strongly deficient)—Abnormal        (associated with deficient amounts of AAT protein)    -   Null—Abnormal (deficient; no AAT protein is detected)

It is the combination of genes that an individual receives from theparents that determines whether he or she is “normal,” is an AATD“carrier” due to inheritance of one abnormal allele, or is severelydeficient in AAT due to inheritance of two abnormal alleles. It isimportant to understand that the disorder can be inherited either from aparent who has AATD or from parents who are carriers but do notthemselves display symptoms of AATD.

Subjects who are identified as AAT deficient carry an increased risk ofdeveloping emphysema. This includes the most frequently observedvariants such as Z and S genotypes. Subjects with the abnormal gene(Null) and no detectable plasma levels of AAT are also at high risk ofdeveloping lung disease. Such individuals with severe AATD are morelikely to manifest clinical symptoms (De Serres, 2002; Luisetti, 2004).

Embodiments of the invention include a genetic diagnostic sampledelivery subsystem for transmitting a genetic specimen from the patientto a genetic diagnostic system configured for diagnosing AAT deficiency.The diagnostic system can detect low plasma serum levels of AAT toprompt use of another subsystem, such as at least one delivery catheter.It has been found that an AAT serum level of less than 35 mg/dl isassociated with AAT deficiency(http://alpha-1foundation.org/testing-for-alpha-1/). The geneticdiagnostic sample delivery subsystem can include a cartridge containerfor storing blood and a needle for collecting a blood sample.

II. Natural History and Progression of the Disease

Severe clinical manifestations of AATD involve the lungs, liver andskin. The signs and symptoms of the condition and the age at which theyappear vary among individuals. AATD is often first inappropriately orincompletely diagnosed as asthma or smoking-related COPD. The risk ofemphysema increases proportionately to the magnitude of deficiency inAAT serum levels. Normal serum levels of AAT range from 150 to 350 mg/dL(Stoller, 1997). Individuals afflicted with AATD have had AAT serumlevels as low as 35 mg/dL.

Most individuals who suffer from advanced AATD experiencehyperinflation. With hyperinflation, the most diseased regions of thelung have normal inspiration but trap air upon expiration. Less affectedor undamaged regions of the lung can then become compressed by thehyperinflated portions. This compression effectively compromises theremaining tissue that is exchanging gas in the lung.

Many features of emphysema due to AATD are similar to those of emphysemain individuals with normal levels of AAT. However, there are threedistinctive features of emphysema associated with AATD described byvarious authors in the literature.

First, although the onset of emphysema is accelerated by smoking,emphysema can occur in AATD patients who have never smoked or beenexposed to other environmental factors, which is exceptionally rareotherwise. Thus this disease is independent of personal choice orenvironmental factors.

Second, AATD patients often develop emphysema when they are in their 30sor 40s, in contrast to patients who are long time smokers but are notAAT deficient. Non-AAT deficient smokers usually do not develop symptomsuntil they are in their 50s or 60s. The mean age at diagnosis ofAATD-associated emphysema was 46 years in the National Heart, Lung andBlood Institute (NHBLI) registry and 50 years in the British ThoracicAssociation series (Stoller, 1997).

Third, the radiographic pattern of AATD emphysema patients differssignificantly from that of AATD-independent emphysema patients (Kaplan,2010). Conventional emphysema due to smoking usually causesemphysematous tissue in the upper parts of the lung. In contrast, AATDemphysema patients show a radiographic pattern of panacinar emphysemapredominant in the lung bases rather than the apex (Holme, 2009).

Additionally, AAT augmentation therapy is prescribed for AATD patientsand pharmacotherapy regimes vary from the more widespread form ofemphysema associated with smoking and/or asthma.

III. Prevalence and Incidence of AATD

AATD is a rare genetic deficiency, with estimates of prevalence rangingfrom 26,000 to 155,000 total affected individuals in the US. See belowfor a summary of available citations and the estimates provided therein(Table 1), collected from scientific and medical peer-reviewed articles,reviews and textbooks; the websites of patient advocacy groups (e.g.,Alpha-1 Foundation); and governmental agency statistics (e.g., Centersfor Disease Control).

Emphysema resulting from AATD generally occurs relatively early in life(in comparison to emphysema pursuant to smoking or occupationalexposure). People develop symptoms in their 30s or 40s in smokers and intheir 40s and 50s for non-smokers (Fregonese, 2008). Life expectancyfrom the time that symptoms appear is approximately 15 years(AllergyCases.org):

“Adults with α1-antitrypsin deficiency present with emphysema in thethird or fourth decade of life. . . . Smokers with α1-antitrypsindeficiency develop symptoms by 30 to 40 years, whereas nonsmokers do notbecome symptomatic until 50 years of age. Mean life expectancy forsmokers is 50 years and 66 years for nonsmokers.”

Thus, to provide the most conservative (i.e. the highest) estimate ofyearly incidence, a life expectancy of 50 years is used in Table I belowto calculate incidence from the cited prevalence values.

TABLE 1 Summary of Prevalence and Incidence Values for AATD Estimate ofEstimate Incidence Statistic Cited in of (individuals/ ReferenceReference Prevalence^(a) year) Kaplan, 2010 1 in 2,000 to 1 in 62,000 to1,240 to 5,000 individuals 155,000   3,100  Alpha-1 Foundation 100,000individuals 100,000   2,000  (www.alpha- with AATD 1foundation.org)Alpha-1 Foundation 1 in 2,500 124,000   2,480  (www.alpha- individuals1foundation.org) www.orpha.net 1 in 5,000 to 1 in 31,000 to   620 to10,000 individuals 62,000  1,240  Luisetti, 2004 310,881 individuals181,800   3,636  with AATD^(b) CDC (Summary 2% of adults 47,000 to   940to Health Statistics for aged 18 and 141,000    2820  U.S. Adults)National over diagnosed Center for with emphysema; Health Statistics1-3% of (Akinbami, 2011) emphysema cases due to AATD^(c) Alpha-1Association 1 in 2,500 124,000   2,480  (www.alpha1.org) individualswith AATD Fregonese, 2008 1 in 2,500 124,000   2,480  AAT Registry100,000 individuals 100,000   2,000  (www.aatregistry.org) with AATDStoller, 1997 60,000 to 100,000 60,000 to 1,200 to individuals with100,000   2,000  AATD

a All estimates assume a U.S. population of 310 million individuals.

b Cited statistic was 257,708 individuals with Pi*S/Pi*Z genotype and53,173 individuals with Pi*Z/Pi*Z genotype in North America, whotogether make up the vast majority of the population with manifest AATdeficiency. Assuming a North American population of ˜530 million and aUS population of 310 million, this suggests ˜150,700 individuals withPi*S/Pi*Z genotype and 31,100 individuals with Pi*Z/Pi*Z genotype in theUS.

c Assumes 235 million adults (aged 18 and over) in the US. 2% of thispopulation yields 4.7 million people diagnosed with emphysema, and 1-3%(47,000 to 141,000) are due to AAT deficiency.

The data summarized in Table 1 above suggests that the incidence of AATDranges from 620 to 3,636 cases per year, with most estimates ofincidence at approximately 2,000 new births per year. Importantly,however, it has been noted that only a small fraction of AATDindividuals have been properly diagnosed. The clinical manifestations ofAATD, including breathlessness, cough, phlegm, wheeze and fatigue,especially in individuals who are non-smokers or never-smokers, leads tofrequent misdiagnosis of AATD as asthma. Kaplan (2010, referencetherein), Sandhaus (2004), and the Alpha-1 Foundation estimate that only5-10% of individuals with AATD have been properly diagnosed. Appliedagainst the estimates of the true incidence rate from Table 1 above (620to 3,636 per year), this suggests that only 31 to 364 cases (100 to 200cases in most estimates) will be diagnosed yearly.

Furthermore, the incidence rates noted above include some earlydiagnoses in individuals who still retain normal lung function anddisplay only mild spirometric obstruction. COPD is rarely seen beforethe age of 30 in AATD, therefore, any proposed intervention that targetshyperinflation or an FEV1<50% predicted, such as the PneumRx AATDTreatment System, would be appropriate for the smaller fraction ofpatients showing these clinical symptoms.

IV. AATD is an Orphan Indication

Consistent with the analysis in Section 3.3, both AATD and AATD-relatedemphysema have been assigned orphan indication status by the FDA. Thesedeterminations, obtained from the FDA Office of Orphan ProductsDevelopment (OOPD) database, are listed in Table 2 below. Though thestandards for demonstrating a rare disease population are different fordrugs [prevalence of fewer than 200,000 individuals, as per 21 CFR316.20(b)(8)(i)] and devices [incidence of fewer than 4,000 individualsper year, as per 21 CFR 814.3(n)], designation of orphan statusindicates that FDA accepts the total prevalence of AATD in the US to befewer than 200,000 individuals. This is in substantial agreement withthe prevalence estimates above (ranging from 26,000 to 181,800individuals in the US), which were derived from scientific and medicalliterature, advocacy groups, and various registries/databases.

TABLE 2 Summary of Orphan Drug Product Designations for AATD by FDADesignation Generic Name Date Indication Alpha-1-Antitrypsin Jan. 1,1984 As supplementation therapy (Recombinant DNA for alpha-1-antitrypsinOrigin) deficiency in the ZZ genotype population. Alpha 1-ProteinaseDec. 7, 1984 For replacement therapy Inhibitor (Human) in thealpha-1-proteinase inhibitor congenital deficiency state. HyaluronicAcid Mar. 19, 2002 Treatment of emphysema in patients due to alpha-1antitrypsin deficiency. Recombinant Secretory Mar. 29, 1991 Treatment ofcongenital Leucocyte Protease alpha-1 antitrypsin Inhibitor deficiency.Transgenic Human May 19, 1999 Treatment of emphysema Alpha 1 Antitrypsinsecondary to alpha 1 antitrypsin deficiency. Alpha 1 Proteinase Jan. 29,2010 Treatment of emphysema Inhibitor (Human) secondary to congenitalalpha 1-antitrypsin deficiency. Alpha 1-Proteinase Nov. 24, 1999 Forslowing the progression Inhibitor (Human) of emphysema in alpha1-antitrypsin deficient patients. Recombinant Adeno- Jan. 27, 2003Treatment of alpha Associated Virus 1-antitrypsin deficiency. Alpha 1-Antitrypsin Vector

Of the four therapeutics approved as augmentation therapies for thetreatment of AATD (discussed in more detail in Section 4 below),Prolastin was approved as an orphan drug.

V. Treatment Options for AATD-Induced Emphysema

Symptomatic patients with AATD-associated emphysema are currentlytreated according to published guidelines for treatment of emphysemawith the addition of augmentation therapy. If applicable, smokingcessation is the first line recommended treatment. Many of the medicaltreatments available for emphysema including medications, supplementaloxygen and pulmonary rehabilitation may be effective for the AATDpopulation. However, there are no existing therapies for relieving orimproving symptoms of AATD-associated emphysema involving the use ofimplants, namely lung volume reduction implants as disclosed herein.Atelectasis inducing implants for non-genetically induced emphysemawould not be useful for AATD-associated emphysema, since empty cavitiestraversing diseased alveoli are not associated with AATD-associatedemphysema to make use of such devices. Hence, there may be a substantialbelief by those skilled in the art that, in general, an implantabledevice for lung volume reduction would not be effective for treatingAATD-associated emphysema.

AATD-associated emphysema can be treated medically with inhaledbronchodilators, inhaled corticosteroids, and supplemental oxygen. Thesepatients are prone to respiratory infections and thus are oftenprescribed antibiotics as well. Pulmonary rehabilitation includesexercise, training, and education. Although lung transplant remains anoption for some patients, this option is considered to be a last resortdue to its high risks. LVRS, an uncommon option in COPD, has not beenshown to be effective in AATD-induced emphysema (Stoller, 2007)).

Because of the genetic deficiency inherent in AATD-associated disease,AATD patients are commonly treated with augmentation therapy (see Table3 below). Augmentation therapy with intravenous administration of humanAAT increases the levels of AAT in the bronchoalveolar lavage fluid ofAATD individuals (ATSERS, 2003). This therapy maintains the serum AATconcentration at levels sufficient to inhibit most HNE. However, incontrast to the proven effectiveness of augmentation treatment, theclinical effect of supplemental AAT on pulmonary function, morbidity andsurvival has been demonstrated only in prospective observationalstudies, but not in randomized controlled trials. Finally, because theseaugmentation therapies (Table 3 below) seek to prevent progression ofemphysema, approvals do not claim improvement in symptoms of emphysemain patients with existing disease.

TABLE 3 Augmentation Therapies for Alpha-1-Antitrypsin Deficiency in theUS. Treatment Prolastin-C ® Aralast ® Zemaira ® Glassia ® ManufacturerTalecris Alpha Aventis Kamada, Ltd. Biotherapeutics, Therapeutic BehringLLC (U.S. rights Inc (now Corp. (now (now acquired by manufacturedmanufactured manufactured Baxter) by Grifols) by Baxter) by CSL Behring)Orphan Status Prolastin has orphan No orphan status No orphan status Noorphan status License BLA; Dec. 2, 1987 BLA; Dec. 23, 2002 BLA; Jul. 8,2003 BLA; Jul. 1, 2010 Indication Adults who Indicated for ChronicGLASSIA is an alpha1- have augmentation augmentation proteinaseinhibitor that emphysema therapy in and is indicated for chronic causedby patients having maintenance augmentation and inherited alpha1-congenital therapy in maintenance therapy in antitrypsin deficiency ofindividuals with adults with emphysema deficiency alpha1-proteinasealpha1- due to congenital inhibitor with proteinase deficiency ofalpha1- clinically evident inhibitor proteinase inhibitor emphysemadeficiency and (Alpha1-PI), also known evidence of as alpha1-antitrypsin emphysema deficiency Contraindications Not indicatedContraindicated in Individuals IgA deficient patients as therapy forindividuals with with selective with antibodies against lung disease inselective IgA IgA IgA; history of severe patients in deficiencies (IgAdeficiencies immediate whom severe level less than 15 who havehypersensitivity Alpha1- PI mg/dL) who have known reactions, includingdeficiency has known antibody antibodies anaphylaxis, to Alpha1- notbeen against IgA, since against IgA PI products established; they mayexperience (anti-IgA IgA deficient severe reactions, antibodies)patients with including should not antibodies anaphylaxis receiveagainst IgA Zemaira should not receive Prolastin-C due to the risk ofhypersensitivity Route of Admin Intravenous Intravenous infusionIntravenous Intravenous infusion infusion infusion Adverse EventsChills, a general Headache, Asthenia, The most common feeling of beingmusculoskeletal injection site product-related adverse unwell, headache,discomfort and pain, reactions (>5%) in rash, hot flush, somnolencedizziness, clinical studies were and itching headache, headache anddizziness paresthesia and pruritus

Unlike augmentation therapy, the embodiments disclosed herein intendedto improve lung function, exercise capacity and quality of life inpatients who have emphysema due to deficiency of genetically relatedemphysema, such as alpha-1 antitrypsin, by achieving a lung volumereduction implant system using minimally invasive means. As noted above,the panacinar sub-type of emphysema is most commonly associated withAATD patients (Holme, 2009). Panacinar emphysema destroys the entirealveolus uniformly and predominantly affects the lower half of thelungs.

Many embodiments include at least one implant that behaves as a springelement that, through compression of diseased tissue, creates tension inthe surrounding healthy lung tissue and may result in restoration ofradial suspension of the lung airway network. By compressing thediseased tissue and providing increased tension and outward radialsupport of airways in the healthy parts of the lung, the implant canreduce air-trapping and help regain diaphragm mobility and muscleactivity, which also supports breathing function.

The implant is available in different lengths. Longer lengths of theimplant to facilitate access to diseased tissue through longer airways,and sufficiently treat the lower lobes, for example 100-150 mm. Thus, animplant may be placed within a middle and/or upper lobe to affecttreatment of a lower lobe. Since AATD emphysema patients show panacinaremphysema predominant in the lung bases, such lengths are anticipated tofacilitate access to the diseased tissue in the lower zones of the lung.Generally, at least one implant is required to affect treatment of alower lobe, however, a plurality of implants can be used. For example,in some cases 8-12 implants can be used. Regardless, it should beunderstood that the number of implants used depends on the particulartype of implant(s), the state of disease in the recipient lung, andimplant location(s). For example, stronger coils can be used withinupper lobes of a lung to affect a diseased lower lobe and/or relativelyweaker coils can be used directly within the lower lobe.

Currently there is no other device or drug available, specifically forthis population, that helps treat the symptoms of AATD-induced emphysemaand improve quality of life for these patients. The augmentationtherapies treat the underlying cause of the disease but do not claim toimprove the clinical symptoms or treat/mitigate lung tissue damage thathas already occurred. Because the implant system is designed to restorelung recoil and improve clinical symptoms, it is expected to improvequality of life for AATD emphysema patients. The two therapies havedifferent mechanisms of action in targeting AATD-dependent emphysema,and it is suggested that the disclosed implant system may be usedconcurrently with augmentation therapy to provide both immediateimprovement in disease symptoms and a delay in progression of thedisease itself (augmentation therapy).

TABLE 4 Potential advantages and benefits of the implant system as atreatment for emphysema due to AATD. Currently Approved Therapies Aspectof (Prolastin-C, Aralast, Zemaira, Therapy Glassia) Implant systemNature of All are drugs within the same Device. Unique therapeutictherapy therapeutic class (augmentation modality with a novel, therapywith purified alpha-1 mechanical Mechanism of antitrypsin). Action(MOA). May be useful in patients who do not respond to augmentationtherapy or for whom augmentation therapy is contraindicated. Risk ofdisease Purified from pooled human plasma No risk of diseasetransmission (possible risk of disease transmission, transmission.including HIV, hepatitis, Parvovirus, or Creutzfeldt-Jakob diseasetransmission). Immune Prolonged treatment may promote No expectation ofimmune response development of antibodies to the response; can be usedfor protein therapy. prolonged treatment. All drugs are contraindicatedin IgA sensitivity would not patients with IgA sensitivity due torestrict implantation of the the possibility presence of IgA in coils.the product (severe hypersensitivity/ anaphylaxis may result). Mechanismof Disease-modifying therapy Symptom-modifying therapy Action (MOA)(replacement of natural alpha-1 (mechanically compresses antitrypsininhibits neutrophil damaged parenchyma and elastase activity in thelung). tenses the surrounding Late diagnosis of AATD is common healthytissue, thereby due to similarity of symptoms to increasing elasticrecoil, asthma and the lack of association reducing hyperinflation, andwith smoking; gap between redirecting air to healthier symptom onset anddiagnosis is portions of the lung). frequently 7 years or more Effectivein ameliorating (Needhan, 2004; Kaplan, 2010). emphysema symptoms, butThus most diagnoses occur in not predicted to be effective patients withsignificant existing in slowing progression of lung damage andsignificant emphysema. emphysema symptoms. PneumRx System MOA isEffective in slowing development or predicted to complement progressionof emphysema due to augmentation therapies unrestrained elastaseactivity, but rather than replace them. not effective in amelioratingexisting emphysema symptoms. Safety Though generally safe, associatedNot predicted to share an AE adverse events (AEs) include profile withavailable asthenia, injection site pain, augmentation therapies. AEsdizziness, headache, paresthesia, associated with the treatmentpruritus, chills, malaise, system placement are similar rash, hot flush,and somnolence. in type and frequency to those seen with bronchoscopyalone (required for deployment of the implants).

TABLE 5 Comparison with Known Therapies Trade Name Prolastin-C ®Aralast ® Zemaira ® Glassia ® Implant System Mechanism BecauseAugmentation Zemaira ® GLASSIA ® is The implant of PROLASTIN ® therapyhas been serves as A1-PI an system is Action “augments” or shown tomaintain augmentation augmentation intended to (MOA) replaces serumlevels of therapy in this therapy that improve lung missing AAT, AATabove the patient serves to function in it is referred ATS/ERS-population, maintain patients with to as recommended acting to serumlevels emphysema by “augmentation protective threshold increase of AATintroducing therapy” or of 11 μM. and maintain nitinol “replacementserum levels and spring coil(s) therapy.” lung epithelial implant(s)into the lining fluid lungs to compress (ELF) levels damaged tissue ofA1-PI. (lung volume reduction) and restore elastic recoil to theremaining undamaged lung tissue via minimally invasive means. Adversechills, a headache, asthenia, The most Bronchoscopy Events generalmusculosk injection site common procedure related feeling of eletalpain, dizziness, product-related adverse events being unwell, discomfortheadache, adverse such as headache, and paresthesia and reactions (>5%)pneumothorax and rash, hot somnolence. pruritus. in clinical infection;immune flush, and studies were reaction to the itching. headache andimplant is rare. dizziness. Pros Effective in slowing progression ofemphysema. Effective in treating the symptoms of emphysema. Cons Becausethis product is made from human plasma, it may carry a risk MOA predictsno of transmitting infectious agents. slowing in The effect of therapywith any ATT on pulmonary exacerbations and on progression of theprogression of emphysema in ATT deficiency has not been emphysema.demonstrated in randomized, controlled clinical trials.

Per the FDA OOPD database, augmentation therapies that boost circulatingAAT plasma levels have been classified under orphan drugs, indicatingthat the FDA has previously determined that the AATD patient populationin the United States is fewer than 200,000 individuals. There areapproximately 100 to 200 new AATD emphysema diagnoses in the U.S. eachyear. The combined estimated incidence of diagnosed and undiagnosed AATDemphysema is 620 to 3636 cases per year. These numbers qualify thedisclosed implant system for a Humanitarian Use Device designation inthis indication.

As shown above, there are several medical treatments available for AATDemphysema patients including augmentation therapy and surgery.Augmentation therapy slows the progression of the underlying damage tothe lung, but is not intended to improve current clinical symptoms ofemphysema. Surgical options, including LVRS and lung transplant surgery,are highly invasive and carry significant safety risks. The disclosedimplant system and the method for use can also have their own relatedadverse events, but the benefits of the implant system outweigh therisks involved, and the device offers unique benefits that are notcurrently available with pharmacotherapy. The implant system can be usedconcomitantly with augmentation therapy or alone in the treatment ofsymptoms from emphysema associated with AATD. The implant system isanticipated to be safe for its intended use using a minimally invasiveprocedure, and, unlike augmentation therapy, the implant system mayprovide relief from emphysema symptoms, unlike augmentation therapy,with a minimally invasive procedure.

VI. Literature References

-   1. AAT Registry. http://www.aatregistry.org/.-   2. Akinbami L J, Liu X. Chronic Obstructive Pulmonary Disease Among    Adults Aged 18 and Over in the United States, 1998-2009. National    Center for Health Statistics Data Brief; June 2011.-   3. AllergyCases.org.    http://allergycases.org/2008/02/alpha-1-antitrypsin-deficiency.html.-   4. Alpha-1 Association. http://www.alpha1.org/.-   5. Alpha-1 Foundation. http://alpha-1foundation.org/.-   6. Alpha-1-antitrypsin-deficiency.    http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency.-   7. American Thoracic Society; European Respiratory Society (ATSERS).    American Thoracic Society/European Respiratory Society statement:    standards for the diagnosis and management of individuals with    alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med Vol 168.    pp 818-900, 2003. http://www.thoracic.org/statements/res    ources/respiratory-disease-adults/alpha1.pdf.-   8. Bronchoscopy. Johns Hopkins Medicine: Health Library.    http://www.hopkinsmedicine.org/healthlibrary/testprocedures/pulmonary/bronchoscopy_92,P07743/.-   9. Bronchoscopy. Medline Plus.    http://www.nlm.nih.gov/medlineplus/ency/article/003857.htm.-   10. de Serres F J. Worldwide racial and ethnic distribution of    alpha1-antitrypsin deficiency: summary of an analysis of published    genetic epidemiologic surveys. Chest. 2002. 122(5): 1818-29.-   11. Fregonese L, Stalk J. Hereditary alpha 1 antitrypsin deficiency    and its clinical consequences. Orphanet Journal of Rare Diseases    2008, 3:16.-   12. Genetic and Rare Diseases website.    http://rarediseases.info.nih.gov/GARD/Default.aspx?PageID=4.-   13. Holme J, Stockley R A. CT scan appearance, densitometry, and    health status in protease inhibitor SZ alpha1-antitrypsin    deficiency. Chest. 2009 Nove; 136(5):1284-1290.-   14. Kaplan A, Cosentino L. Alpha1-antitrypsin deficiency: forgotten    etiology. Can Fam Physician. 2010 January; 56(1):19-24.-   15. Kumar V, Abbas A K, Fausto N, ed. (2005). Robbin and Cotran    Pathological Basis of Disease (7th ed.). Elsevier/Saunders: 911-2.-   16. Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1:    epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004    February; 59(2):164-9.-   17. National Center for Health Statistics Data Brief. Chronic    Obstructive Pulmonary Disease Among Adults Aged 18 and Over in the    United States, 1998-2009; June 2011.-   18. National Heart, Lung and Blood Institute, U.S. Department of    Health and Human Services.    http://www.nhlbi.nih.gov/health/health-topics/topics/bron/risks.html.    Feb. 8, 2012.-   19. Needham M, Stockley R A. Alpha 1-antitrypsin deficiency. 3:    Clinical manifestations and natural history. Thorax. 2004 May;    59(5):441-5. Review.-   20. Office of Orphan Products Development (OOPD).    http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm.    Feb. 8, 2012-   21. Orphanet. http://www.orpha.net/consor/cgi-bin/index.php.-   22. Piitulainen E, Eriksson S. Decline in FEV1 related to smoking    status in individuals with severe alpha1-antitrypsin deficiency    (PiZZ). Eur Respir J. 1999 February; 13(2):247-251.-   23. Russi E W. Alpha-1 antitrypsin: now available, but do we need    it? Swiss Med Weekly. 2008 Apr. 5; 138(13-14):191-6.-   24. Sandhaus R A. a1-Antitrypsin deficiency? 6: New and emerging    treatments for a 1-antitrypsin deficiency. Thorax 2004;    59(10):904-909.-   25. Sotller, J K, Gildea, T R, Ries, A L, Meli, Y M, Karafa, M T,    Lung Volume Reduction Surgery in Patients with Emphysema and alpha-1    Antitrypsin Deficiency, Ann. Thoracic Surg. 2007; 83:241-251.-   26. Summary Health Statistics for U.S. Adults: National Health    Interview Survey, 2010; Vital and Health Statistics, CDC series    10#252, January 2012; 30-36.

By way of background and to provide context for embodiments herein, FIG.1A illustrates the respiratory system 10 located primarily within athoracic cavity 11. This description of anatomy and physiology isprovided in order to facilitate an understanding of the invention.Persons of skill in the art will appreciate that the scope and nature ofthe invention is not limited by the anatomy discussion provided.Further, it will be appreciated there can be variations in anatomicalcharacteristics of an individual, as a result of a variety of factors,which are not described herein. The respiratory system 10 includes thetrachea 12, which brings air from the nose 8 or mouth 9 into the rightprimary bronchus 14 and the left primary bronchus 16. From the rightprimary bronchus 14 the air enters the right lung 18; from the leftprimary bronchus 16 the air enters the left lung 20. The right lung 18and the left lung 20 together comprise the lungs 19. The left lung 20 iscomprised of only two lobes while the right lung 18 is comprised ofthree lobes, in part to provide space for the heart typically located inthe left side of the thoracic cavity 11, also referred to as the chestcavity.

As shown in more detail in FIG. 1B, the primary bronchus, e.g. leftprimary bronchus 16, that leads into the lung, e.g. left lung 20,branches into secondary bronchus 22, and then further into tertiarybronchus 24, and still further into bronchioles 26, the terminalbronchiole 28 and finally the alveoli 30. The pleural cavity 38 is thespace between the lungs and the chest wall. The pleural cavity 38, shownin FIG. 1C, protects the lungs 19 and allows the lungs to move duringbreathing. Also shown in FIG. 1C, the pleura 40 defines the pleuralcavity 38 and consists of two layers, the visceral pleurae 42 and theparietal pleurae 44, with a thin layer of pleural fluid therebetween.The space occupied by the pleural fluid is referred to as the pleuralspace 46. Each of the two pleurae layers 42, 44, are comprised of veryporous mesenchymal serous membranes through which small amounts ofinterstitial fluid transude continually into the pleural space 46. Thetotal amount of fluid in the pleural space 46 is typically slight. Undernormal conditions, excess fluid is typically pumped out of the pleuralspace 46 by the lymphatic vessels.

The lungs 19 are described in current literature as an elastic structurethat floats within the thoracic cavity 11. The thin layer of pleuralfluid that surrounds the lungs 19 lubricates the movement of the lungswithin the thoracic cavity 11. Suction of excess fluid from the pleuralspace 46 into the lymphatic channels maintains a slight suction betweenthe visceral pleural surface of the lung pleura 42 and the parietalpleural surface of the thoracic cavity 44. This slight suction creates anegative pressure that keeps the lungs 19 inflated and floating withinthe thoracic cavity 11. Without the negative pressure, the lungs 19collapse like a balloon and expel air through the trachea 12. Thus, thenatural process of breathing out is almost entirely passive because ofthe elastic recoil of the lungs 19 and chest cage structures. As aresult of this physiological arrangement, when the pleura 42, 44 isbreached, the negative pressure that keeps the lungs 19 in a suspendedcondition disappears and the lungs 19 collapse from the elastic recoileffect.

When fully expanded, the lungs 19 completely fill the pleural cavity 38and the parietal pleurae 44 and visceral pleurae 42 come into contact.During the process of expansion and contraction with the inhaling andexhaling of air, the lungs 19 slide back and forth within the pleuralcavity 38. The movement within the pleural cavity 38 is facilitated bythe thin layer of mucoid fluid that lies in the pleural space 46 betweenthe parietal pleurae 44 and visceral pleurae 42. As discussed above,when the air sacs in the lungs are damaged 32, such as is the case withemphysema, it is hard to breathe. Thus, isolating the damaged air sacsto improve the elastic structure of the lung improves breathing.Similarly, locally compressing regions of the lung tissue whilemaintaining an overall volume of the lung increases tension in otherportions of the lung tissue, which can increase the overall lungfunction.

A conventional flexible bronchoscope is described in U.S. Pat. No.4,880,015 to Nierman for Biopsy Forceps. As shown in FIGS. 2A-D,bronchoscope 50 can be configured to be of any suitable length, forexample, measuring 790 mm in length. The bronchoscope 50 can further beconfigured from two main parts, a working head 52 and an insertion tube54. The working head 52 contains an eyepiece 56; an ocular lens with adiopter adjusting ring 58; attachments for the suction tubing 60 and asuction valve 61 and for the cold halogen light source 62 and 63; and anaccess port or biopsy inlet 64, through which various devices and fluidscan be passed into the working channel 66 and out the distal end of thebronchoscope. The working head is attached to the insertion tube, whichtypically measures 580 mm in length and 6.3 mm in diameter. Theinsertion tube can be configured to contain fiberoptic bundles (whichterminate in the objective lens 67 at the distal tip 68), two lightguides 70, 70′ and the working channel 66. The distal end of thebronchoscope has the ability to bend 72 anterior and posterior, with theexact angle of deflection depending on the instrument used. A commonrange of bending is from 160 degrees forward to 90 degrees backward, fora total of 250 degrees. Bending may be controlled by the operator byadjusting an angle lock lever and angulation lever on the working head.See also, U.S. Patent Pub. US 2005/0288550 A1 to Mathis for Lung AccessDevice and US 2005/0288549 A1 to Mathis for Guided Access to LungTissue, which is incorporated herein by reference.

FIG. 3 illustrates the use of a lung volume reduction delivery device 80for delivering a lung volume reduction device comprising an implantabledevice with the bronchoscope 50. The lung volume reduction system, asdescribed in further detail below, is adapted and configured to bedelivered to a lung airway of a patient in a delivery configuration andthen transitioned to a deployed configuration. By deploying the device,tension can be applied to the surrounding tissue which can facilitaterestoration of the elastic recoil of the lung. The device is designed tobe used by an interventionalist or surgeon.

FIGS. 4A-F illustrate a shaft or tubular member of a lung volumereduction device 110 which may be included in an implant according to anaspect of the invention, with FIGS. 4B-F being cross-sections takenalong the lines B-B, C-C, D-D, E-E, and F-F of FIG. 4A, respectively.The lung volume reduction device 110 includes a member, such as tubularmember 112, which has c-cuts 114, or notches, along its length toprovide flexibility such that the device can be deflected off alongitudinal axis A when deployed. In other words, the longitudinal axisof the implant shaft or body may be changed from a generally straightconfiguration suitable for distal insertion along axis A to a bent ordeployed configuration. The bent or deployed implant may bend orreconfigure a surrounding airway so as to locally compress lung tissue.For example, where the cuts are oriented parallel to one another alongthe length of the tubular member and are of the same or similar depth D,the device will tend to uniformly curve around an axis point whendeployed. As a result, the device preferentially curls or bends in adirection as determined by the shape of the slots. Different types(width, depth, orientation, etc.) of notches or slots can be used toachieve different operational effects and configurations of the deployeddevice without departing from the scope of the invention.

Positioned within a lumen 113 of the tubular member 112, is an actuationelement 116 or pull-wire. The actuation element can have a circularcircumference in cross-section, as depicted, or can have any othersuitable cross-section. The actuation element 116 may be anchored at oneend of the device 110, e.g. the distal end, by a cap 119. The cap 119can be bonded to the device and a distal crimp can be provided to crimpthe cap 119 into the pull-wire 116. The cap 119 may be rounded asdepicted to make the dip of the device atraumatic. Alternatively, cap119 may be configured to include an anchor configured to grasp theadjacent airway during the device deployment within the airway. Theanchor may increase the amount of tissue compression by a deployeddevice and thereby increase the amount of beneficial tension in thelung. Such optional anchors are discussed further below. The opposingend, e.g. proximal end, may be adapted and configured to engage amechanism 120. The mechanism 120 may be adapted deploy the device.Further mechanism 120 may be configured to lock the device into adeployed configuration once the device 110 is deployed or to unlock thedevice to facilitate retrieval of the device from an airway. The device110 may be configured to be detachable from a delivery catheter adaptedto deliver the lung volume reduction device. The delivery catheter anddelivery of the device are discussed further below.

Mechanism 120, at the proximal end of the device may be adapted toinclude a retainer ring 122 that engages a ratchet 124 that can be usedto lock the device in place. The coupler 126 retains the ratchet 124such that the ratchet locks the device in place once deployed. At theproximal end, a retrieval adapter 130 is provided, such as a pull-wireeyelid. The retrieval adapter 130 may be adapted and configured toenable the device to be retrieved at a later point during the procedureor during a subsequent procedure. The ratchet device may include flangesthat extend away from a central axis when deployed to lock the device inplace.

FIGS. 5A-C illustrate yet another lung volume reduction device accordingto another aspect of the invention, with FIGS. 5B-C being cross-sectionstaken along the lines B-B, and C-C of FIG. 5A, respectively. As depictedin this embodiment, the lung volume reduction device 310 includes amember, such as tubular member 312, which has c-cuts 314, 314′, ornotches, along its length to provide flexibility such that the devicecan be deflected in more than one direction off a longitudinal axis Awhen deployed. In this embodiment, the notches are positioned on themember 312 on opposing sides of the member when the member is lyingwithin a plane. For example, where the cuts are oriented parallel eachother along the length of the tubular member and are of the same orsimilar depth D, the device will tend to uniformly curve around an axispoint when deployed. In this embodiment, when deployed, theconfiguration of the notches would result in a deployed configurationthat is “s-shaped” when the actuator element 316 is pulled proximally(i.e., toward the user).

FIG. 6 illustrates yet another lung volume reduction device 410according to another aspect of the invention. In this embodiment, thetubular member 412 has notches 414, 414′, 414″ configured in a spiralpattern along its length. As a result, when the actuation element 416 ispulled proximally toward the user, the device bends to form a spiral asillustrated below.

FIG. 7 illustrates a lung volume reduction device 510 encased in asheath 535. The sheath can be a polymeric elastic membrane, such assilicone. The sheath can prevent material from a body cavity fromentering the lumen 513 of the tubular member 512. An actuation member516 is provided within the lumen 513 of the tubular member 512.

FIGS. 8A-D illustrate yet another lung volume reduction device 610according to another aspect of the invention, with FIGS. 8B-D beingcross-sections taken along the lines B-B, C-C, and D-D of FIG. 8A,respectively. The lung volume reduction device 610 in this embodiment iscomprised of individual segments 612, 612′, 612″. The segments can beconfigured, for example, to have identical asymmetrical configurationssuch that a compressible space 614 is between each segment before thedevice is actuated by activating the actuator element 616. Each of thesegments can further comprise a detent on a first surface which opposesa mating indentation on a surface of an opposing segment. As will beappreciated, a variety of components of devices disclosed herein can beconfigured to provide locking or mating mechanisms to facilitateactuation and operation. When the actuation element 616 is activated,the compressible space is reduced and the opposing surfaces of twoadjacent segments come together to reduce or eliminate the space betweenthem, depending upon the desired outcome. Where the segments haveidentical or nearly identical configurations, the device will evenly arcaround an axis point. Where the segments do not have identicalconfigurations, a variety of configurations can be achieved upondeployment depending on the configurations of the segments selected andthe organization of the segments in the device. As with previousembodiments, the actuator element 616 is secured at one end, e.g., thedistal end, by a cap 619. The segments can be formed as hypotubes or canbe formed as injection molded or solid pieces. Use of segments can avoidfatigue on the device because the surfaces come in contact with oneanother during compression. Material selection can also preventbiometallic corrosion. Further, the segment design is conducive for massproduction and maintenance of consistence for final shape and operation.

FIGS. 9A-B illustrate segments 712, 712′ suitable for use in configuringa lung volume reduction device according to an aspect of the invention.The segments, as depicted, can be generally cylindrical with a pair ofsurfaces that are either parallel or non-parallel each other at eitherend. To achieve the operation described above, a first surface 713 couldbe perpendicular to the elongated tubular sides 715 of the element,while the opposing surface 717 is not perpendicular to the sides of theelement (or parallel to the opposing first surface). A detent 721 can beprovided on one surface that is configured to mate with an indentation723 the second surface of another. Other configurations, such as a key:keyway combination, can be used without departing from the scope of theinvention. A central lumen 725 is provided through which an actuatorelement (described above) passes through. I

FIG. 10 illustrates devices 2510 according to the invention in apre-deployed configuration. FIG. 10 illustrates the device 2510 having alongitudinal configuration, such as the configuration assumed prior todeployment. When the device is implanted and placed in compression ortension axially, the device will preferentially bend. The actualpreferential bending will vary depending upon the configuration of thedevice. For example, the location, depth, and orientation of the slotsdepicted in FIGS. 4-7; or the orientation of the walls of the segmentsof FIG. 8. As will be appreciated by those skilled in the art uponreviewing this disclosure, other configurations can be achieved by, forexample, altering the size and location of the c-cuts on the tubularmember, or by altering the configuration of the segments illustrated inFIGS. 8-9. Once the device preferentially bends, the device imparts abending force on the lung tissue which results in a reduction of lungvolume. As is appreciated, the implant, once re-shaped, is shorter inlength than the deliverable implant configuration. The shortening occurswhen for example, the distance between the proximal end and the distalend is reduced. Typically, the deliverable shape of the device is suchthat it fits within a cylindrical space that is 18 mm in diameter orsmaller. Thus, the implant can come into contact with tissue that islarger than 10⁻⁶ square inches per linear inch of the implant length.The re-shaped or deployed implant can be configured in a variety ofshapes to lie within a single plane, or to adopt any other suitableconfiguration, such that it does not lie within a single plane.Additionally, the device can have varying rates of curvature along itslength.

Turning to FIGS. 11A-B, a lung volume reduction device 210 according toanother aspect of the invention is depicted, with FIG. 11B being a crosssection taken along the lines B-B of FIG. 11A. Positioned within a lumen213 of the tubular member 212 is an actuation element 216 or a pullwire. As described above, the actuation element can have a circularcircumference in cross-section, as depicted, or can have any othersuitable cross-section. The actuation element 216 may be anchored at oneend of the device 210, e.g. the distal end, by a cap 219. In thisembodiment, the retainer ring 222 is configured to provide anchors 223,223′ or teeth that are adapted to deploy by retracting the retainingsheath of a delivery catheter. When deployed, the anchors 223 contactthe airway and affix the device in place. The anchor 223 can beconfigured to be self-expanding such that the anchors approach or extendthrough (e.g., hook) the airway. The amount of expansion of the anchorswill be controlled by the design and the materials used. For example,where a shape memory material is used, the anchors can be configured toextend away from the longitudinal wall of the tubular member by apredetermined angle α, as depicted ˜10 degrees. The design of the anchorcan further be driven by the length of the device. The anchors can beconfigured to catch on the airway when deployed in a manner similar tothe way a stent catches within the vasculature, or the anchor can bedesigned to cause friction. Prior to deployment, the anchors may beretained by a retaining sheath (illustrated below).

FIGS. 12A-C illustrates devices 2710 according to the inventionimplanted within, for example, a bronchiole 26. The device 2710 depictedin FIG. 12A is configured to provide an atraumatic tip 2711 on eitherend of the device. When the device 2710 is activated within thebronchiole 26 the device curves and imparts a bending force on the lungtissue. As a result of the bending pressure, the tissue curves andcompresses upon its self to reduce lung volume. Additionally, deploymentof the device can result in the airway becoming bent. As illustrated inFIG. 33C the device can also be configured with a single atraumatic tipso that the deployment mechanism 2720 can easily interface with theproximal end of the device. Alternatively, atraumatic tip 2711 may becomprise a rounded tip similar to the tip illustrated in FIG. 4A.

In another embodiment of the invention, as illustrated in FIGS. 13A-F,the device 810 is comprised of a plurality of individual wires formed ofshape memory material that resume their shape when implanted. The wirescan be heat treated to assume a specific shape, such as a C shape asdescribed above. The wires are then individually implanted through adelivery system 850 such that when the first wire is implanted thediameter of the wire may be small enough that the wire cannot overcomethe force applied by the surrounding tissue to assume its pre-configuredshape. However, upon implantation of additional wires, the amount ofstrength available cumulatively among the wires does overcome the forceapplied by the tissue and the wires, together, achieve the desired shape(see. FIG. 13F). As will be apparent to those of skill in the art, thestrength of a shaped wire can vary depending on how much material isused. For example, a shaped wire with a larger cross-section will havehigher strength than a shaped wire with a smaller cross-section.However, a larger diameter wire may be harder to implant because itwould be harder to straighten into a shape suitable for deployment.Where many small wires are used, each wire individually is more flexibleand can be deployed easier, but as a larger number of wires areimplanted the combined strength increases. In some embodiments, it maybe useful to configure the devices 810 such that the use of, forexample, 50-100 wires will have the strength to overcome pressureapplied by the tissue. The wires 810 can be deployed within a flexiblepolymer tube to keep the wires in proximity to each other.

FIG. 14 shows an example of an implantable device 3703 made from Nitinolmetal wire 3701. Nickel-Titanium, Titanium, stainless steel or otherbiocompatible metals with memory shape properties or materials withcapabilities to recover after being strained 1% or more may be used tomake such an implant. Additionally, plastics, carbon based composites ora combination of these materials would be suitable. The device is shapedlike a French horn and can generally lie in a single plane. The ends areformed into a shape that maximizes surface area shown in the form ofballs 3702 to minimize scraping or gouging lung tissue. The balls may bemade by melting back a portion of the wire, however, they may beadditional components that are welded, pressed or glued onto the ends ofwire 3701.

A Nitinol metallic implant, such as the one illustrated in FIG. 14, maybe configured to be elastic to recover to a desired shape in the body asany other type of spring would or it can be made in a configuration thatmay be thermally actuated to recover to a desired shape. Nitinol can becooled to a martensite phase or warmed to an austenite phase. In theaustenite phase, the metal recovers to its programmed shape. Thetemperature at which the metal has fully converted to an austenite phaseis known as the Af temperature (austenite final). If the metal is tunedso that the Af temperature is at body temperature or lower than bodytemperature, the material is considered to be elastic in the body and itwill perform as a simple spring. The device can be cooled to induce amartensite phase in the metal that will make the device flexible andvery easy to deliver. As the device is allowed to heat, typically due tobody heat, the device will naturally recover its shape because the metalis making a transition back to an austenite phase. If the device isstrained to fit through a delivery system, it may be strained enough toinduce a martensite phase also. This transformation can take place withas little as 0.1% strain. A device that is strain induced into amartensite phase will still recover to its original shape and convertback to austenite after the constraints are removed. If the device isconfigured with an Ar temperature that is above body temperature, thedevice may be heated to convert it to austenite and thermally activateits shape recovery inside the body. All of these configurations willwork well to actuate the device in the patient's lung tissue. The humanbody temperature is considered to be 37 degrees C. in the typical humanbody.

FIG. 15 illustrates a cutaway view of a delivery cartridge system 3800that constrains the implant device 3703 in a deliverable shape. Thedevice 3801 may be shipped to the intended user in such a system or itmay be used as a tool to more easily load the implant into a desiredshape before being installed into the patient, bronchoscope or acatheter delivery device. The cartridge may be sealed or terminated withopen ends or one or more hubs such as the Luer lock hub 3802 that isshown. The implant should be constrained to a diameter that is the sameor less than 18 mm diameter because anything larger than that will bedifficult to advance past the vocal cord opening.

FIG. 16 illustrates another implant device 3901 that is shaped in athree dimensional shape similar to the seam of a baseball. The wire isshaped so that proximal end 3902 extends somewhat straight and slightlylonger than the other end. This proximal end will be the end closest tothe user and the straight section will make recapture easier. If it werebent, it may be driven into the tissue making it hard to access.

FIG. 17 is an illustration of another implant system 4001. It is similarto that shown in FIG. 16 with the addition of a wire frame 4002surrounding the device. The wire frame may be used, for example, toincrease the bearing area that is applied to the lung tissue. Byincreasing the bearing area, the pressure born by the tissue is reducedalong with a reduction in the propensity for the device to grow throughlung structures or cause inflammatory issues. Small wires that applyloads in the body tend to migrate so we believe that the device shouldbe configured to possess more than 0.000001 (1⁻⁶ in²) square inches ofsurface area per linear inch of the length of the device. The frame isone of many ways to provide a larger surface area to bear on the tissue.

FIG. 18 shows yet another example of a device 4101 according to theinvention. The device 4101 features a covering to increase bearing area4102. In this example, the main wire 3902 is covered by a wire frame anda polymeric covering 4102. The covering may be made of any biocompatibleplastic, thermoplastic, fluoropolymer, Teflon®, urethane, metal mesh,coating, silicone or other resilient material that will reduce thebearing pressure on the lung tissue. The ends of the covering 4103 mayremain sealed or open as shown to allow the user to flush antibioticsinto and out of the covering.

FIG. 19 illustrates another configuration of the implant device 4201showing a covering 4205 with perforations 4203 adapted and configured toallow the device to be flushed. The ends 4202 of the covering are sealedto the ends of the device to keep the two components fixed and preventsliding of one or the other during deployment. The covering may bethermally bonded, glued or shrunk to a tight fit.

FIG. 20 illustrates a device 4301 that has the wire frame 4002 joined tothe ball ends 3702 at a junction 4302. The balls may be melted from thewire stock and the wire frame may be incorporated into the ball at thattime. It may also be glued, pressed together, welded or mechanicallylocked together.

FIG. 21 illustrates another implant device 4401 with an attached wireframe 4302, main wire 4103 and a covering 4102. The complete implant mayinclude additional structures or materials which enhance the ability ofthe implant to provide therapeutic benefits during long-termimplantation, with many of these additional structures or materialsproviding a bearing surface or interface between thecompression-inducing shaft of the device and the surrounding tissuelumen wall of an airway. These additional structures or materials may beany of the structures or materials that are disclosed in related U.S.patent application Ser. No. 12/782,515 filed on May 18, 2010, entitledCross-Sectional Modification During Deployment of an Elongate LungVolume Reduction Device, which is incorporated herein by reference.

FIG. 22 illustrates a system of one or more devices that can be hookedtogether 4501. The device 3703 is configured such that it terminates onboth ends, for example, with blunt ball shaped ends 3702. The device4502 is terminated on one end with an open cup and slot shape 4503 thatallows the devices to be coupled together. These devices may bedelivered together or coupled in-situ. Devices may be installed into asingle duct in the lung or in different locations that may be linkedtogether.

FIG. 23 illustrates another three dimensional device 4601 made in theform of a coil with atraumatic ball terminations 3702.

FIGS. 24A-E illustrate another 100 mm long device 900 in apre-implantation or a post-implantation configuration. In thisconfiguration, device 900 includes two helical sections 902, 904 with atransition section 906 disposed between the two helical sections 902,904. Similar to the devices described above, device 900 may have anotherconfiguration which corresponds to a delivery configuration in which thedevice assumes during delivery to a treatment region within an airway.Each helical section 902, 904 includes a respective helical axis 906,908. In the embodiment shown in FIGS. 24A-E, helical axis 906 is at anangle with helical axis 908. In alternative embodiments, helical section902, 904 may share a helical axis.

In this particular embodiment, device 900 comprises a shape-memorymaterial, however a person of ordinary skill would recognize that manyof the methods described above may be used to configure a device suchthat it may be mechanically actuated and locked into a similarconfiguration. Device 900 as shown in the figures includes aright-handed helical section and a left-handed helical section and thetransition section 910 between the two helical sections comprises aswitchback transition section when the device is in the pre-implantationor post-implantation configuration. The switchback transition sectionmay reduce the recoil forces during device 900 deployment therebyproviding greater control of device 900 during deployment. Additionally,the switchback transition may reduce migration of the implant afterdeployment and thus maintain the device's tissue compression advantages.As shown in FIGS. 24A-E, the helical sections do not have to include thesame number of loops or complete helix turns. In this embodiment thedistal helix 904 comprises more loops than the proximal helix 902.Alternatively, device 900 may be configured such that the proximal helix902 includes more loops than distal helix 906. The helical sections maybe configured to include a pitch gap of 0.078±0.025 in. In thisparticular embodiment, the two helical sections are circular helicalsections. Other embodiments of the present invention may be configuredto include spherical or conical helical sections when in apre-implantation or post-implantation configuration.

FIGS. 25A-D illustrate device 900 further comprising a jacket 916.Jacket 916 may increase the diameter of device 900 so as to provide morearea per unit force when deployed in the airway. For example, the jacketmay increase the device diameter by 3.25× to provide more area per unitforce. Accordingly, the increase in diameter may reduce erosion into anairway wall once device 900 is deployed. Jacket 916 may comprise 55Dpolycarbonate urethane (PCU). PCU may reduce biofilms that promotebacterial growth thereby limiting incidents of infection. The jacket maycover the proximal helix, the distal helix, and the transition sectiondisposed between the helices. Additionally, the jacket may cover thedistal portion of the device as shown in FIGS. 25A-D. In someembodiments, the proximal end is also covered by the jacket.Alternatively, the jacket may cover only certain portions of the device.The jacket may be fastened to device 900 by an adhesive such as Loctite3311.

The proximal end 912 and distal end 914 of device 900 may be configuredto be atraumatic. In the depicted embodiment, proximal end 912 anddistal end 914 comprises a ball with a diameter of about 0.055±0.005 inwhich may be made by melting back a portion of the wire or may beadditional components that are welded, pressed or glued onto the ends ofthe wire. The atraumatic ball may have a smaller surface area to allow alow catheter friendly profile or a larger ball which reduces the tissuestress with the larger surface area. In other embodiments, an anchor maybe used to couple the proximal end or distal end of device 900 to anairway wall during the deployment of the device.

Proximal end 912 is also configured as a stand-off proximal tail whichmay be defined by an outer cylindrical boundary defined by the distalcoil. For example, as shown in FIG. 24B, angle θ may be 76°±20°. In someembodiments the stand-off proximal tail may extend away from the axis ofa helical section when the device is in the pre-implantation orpost-implantation configuration as shown in FIG. 24D. The stand-offproximal tail may include a steeper bend 915 at the proximal end whichmay allow more length to be used in compression. Additionally, thestandoff proximal tail provides for better device retrievability oncedeployed by reducing the chances that the proximal tail will impingeagainst or penetrate through the airway wall once the device isdeployed. Accordingly, device repositioning and/or removal may befacilitated by a device with a standoff proximal tail configuration. Thestand-off proximal tail may be used with other device configurations. Inone embodiment, the stand-off proximal tail may be utilized with adevice configuration comprising a single helical section.

FIGS. 26A-E illustrate device 1000 which is similar to device 900.Device 1000 includes a proximal helical section 1002 and a distalhelical section 1004. A transition 1006 is disposed between the twohelical sections 1002, 1004. The proximal end 1012 and distal end 1014comprise atraumatic balls. Distal helical section 1004 includes 4.25loops but may comprise more. FIGS. 27A-D illustrate device 1000 furthercomprising jacket 1016. The distal helical sections may further compressportions of the lungs when device 1000 is deployed within an airway.Similar to device 900, other configurations of device 1000 are possible.For example, device 1000 may be configured to include two right handedhelical sections or two left handed helical sections. Optionally, thehelical sections may share the same helical axis.

FIGS. 28 and 29 illustrate how the device length is reduced when thedevice is deployed in-situ. The device shown in the deliveryconfiguration 4802 in FIG. 28 is also shown in the deployedconfiguration 4803 in FIG. 29. The distance A between the device ends3702 is large while the device is constrained by the constrainingcartridge device 3801. Distance A is similar when the device isconstrained by a loading cartridge, catheter or bronchoscope. FIG. 29shows the same device in a deployed configuration 4803 in an airway 4801that has been deformed by the shape recovery of the implant device. FIG.29 shows that the distance B between the device ends 3702 issubstantially shorter after the device is deployed. Similarly, FIG. 30illustrates the device of FIGS. 26A-E deployed within an airway. As canbe seen, the airway lining may be pinched between adjacent helix loopsthereby providing beneficial tissue compression. In some embodiments, a70% improvement in volume reduction over current LVRC can be obtained.

FIGS. 30 and 31 show two photos of a human lung in a chest cavitysimulator. The lungs were explanted from a person who expired due tochronic obstructive pulmonary disease (COPD). The cavity is sealed withthe lung's main stem bronchi protruding through a hole in the cavitywall. The bronchi has been sealed to the hole so a vacuum can be appliedto aspirate the air from the space between the cavity interior and thelung. This allows the lung to be drawn to a larger expanded conditionwith vacuum levels that are physiologic (such as 0.1 to 0.3 psi, similarto that of the typical human chest cavity). FIG. 30 illustrates a 175 mmlong implant that has been delivered to a distal end of a deliverycatheter as described above. The catheter is substantially constrainingthe implant in a straightened delivery configuration.

FIG. 31 shows the implant after the catheter has been retracted from theimplant to allow the implant to return toward its relaxed configuration.The implant has recovered to its original shape by means of elasticrecoil and possibly a Nitinol metal compositional phase changesubstantially back to austenite. The delivery grasper has been unlockedto release the implant in the airway. By comparing the lung tissue inFIGS. 30 and 31, the regions of the lung that are compressed by theimplant during the process of shape recovery (changing from a deliveredshape to a deployed shape) can be identified. The compressed regions arevisualized in the fluoroscopic images by distinct increases in darknessor darker grey shades of the images. Darker regions identify more denseregions and lighter identify less dense regions. The implant can be seento compress regions as it recovers to cause areas of the lung to becomedarker. Other regions can be seen to be strained or stretched and thiscan also be seen as regions that are converted to a lighter region.

The implant can be placed in pathologic regions in the lung that providelimited or no exchange of gas to and from the blood stream because thealveolar walls used to do so have been degraded by disease due todegeneration of elastin. These are typically the most degraded regionsthat have lost mechanical strength and elasticity. In an inhaling COPDpatient these degraded areas fill with air first, at the expense of gasfilling in regions that could better help the patient, because theweakened tissue presents little to no resistance to gas filling. Byimplanting the devices in these areas, resistance is provided so the gasis filled in regions that still can effectively exchange elements to andfrom the blood stream. Viable regions have structure remaining soresistance to gas filling is present as this is a normal physiologicproperty. The implant advantageously provides more gas fillingresistance in the destroyed regions than the normal physiologicresistance in the viable regions so gas flows to viable tissue. Thiseliminates or reduces the counterproductive “preferential filling”phenomenon of the most diseased lung tissue prior to treatment. However,as mentioned above, the implant can be placed in non-diseased regions inthe lung to affect diseased portions of the lung. Thus, the implant maybe placed within a middle and/or upper lobe to affect treatment of alower lobe.

The implantable device may also delay collapse of airways during abreathing cycle thereby limiting the amount of air trapping in a lung.Accordingly, patients with small airway disease or with alpha1-antitrypsin deficiency may also be treated with such a device.Additionally, the implantable device may be configured to provideenhanced breathing efficacy immediately after implantation while stillallowing gas exchange distal to the deployed implant thereby reducingthe chance of atelectasis of lung tissue distal to the implant.

As with previous embodiments, the embodiments depicted in FIGS. 14-31are adapted and configured to be delivered to a lung airway of a patientin a delivery configuration and to change to a deployed configuration tobend the lung airway. The devices are characterized in that the deviceshave a delivery configuration that is resiliently bendable into aplurality of shapes, such as the ones depicted in the Figures. Thedesign of the devices can be such that strain relief is facilitated onboth ends of the device. Further the ends of the device in either thedelivery or deployed state are more resilient.

The devices can have any suitable length for treating target tissue.However, the length typically range from, for example, 1 to 20 cm. Thediameter of the device can range from 1.00 mm to 1.5 mm, 1.00 to 3.0 mm,and in some embodiments 2.4 mm. The device is used with a catheter whichhas a working length of 60 cm to 200 cm, preferably 90 cm.

In operation the devices shown in FIGS. 14-31 are adapted and configuredto be minimally invasive which facilitates easy use with a bronchoscopeprocedure. Typically, there is no incision and no violation of thepleural space of the lung during deployment. Furthermore, collateralventilation in the lung does not affect the effectiveness of theimplanted device. As a result, the devices are suitable for use withboth homogeneous and heterogeneous emphysema.

Each of the devices depicted in FIGS. 14-31 are adapted and configuredto impart bending force on lung tissue. For example, a spring elementcan be provided, as illustrated in FIG. 14 that imparts bending force onlung tissue. The implantable spring element that can be constrained intoa shape that can be delivered to a lung airway and unconstrained toallow the element to impart bending force on the airway to cause theairway to be bent.

Embodiments of the lung volume reduction system can be adapted toprovide an implant that is constrained in a first configuration to arelatively straighter delivery configuration and allowed to recover insitu to a second configuration that is less straight configuration.Devices and implants can be made, at least partially, of spring materialthat will fully recover after having been strained at least 1%, suitablematerial includes a metal, such as metals comprising Nickel andTitanium. In some embodiments, the implant of the lung volume reductionsystem is cooled below body temperature in the delivered configuration.In such an embodiment, the cooling system can be controlled by atemperature sensing feedback loop and a feedback signal can be providedby a temperature transducer in the system. The device can be configuredto have an Af temperature adjusted to 37 degrees Celsius or colder.Additionally, at least a portion of the metal of the device can betransformed to the martensite phase in the delivery configuration and/orcan be in an austenite phase condition in the deployed configuration.

Lung volume reduction systems, such as those depicted in FIGS. 14-31,comprise an implantable device that is configured to be deliverable intoa patient's lung and which is also configured to be reshaped to make thelung tissue that is in contact with the device more curved. Increasingthe curvature of the tissue assists in reducing the lung volume ofdiseased tissue, which in turn increases the lung volume of healthiertissue. In some instances, the devices are configured to be reshaped toa permanent second configuration. However, as will be appreciated bythose skilled in the art, the devices can also be adapted and configuredto have a first shape and is configured to be strained elastically to adeliverable shape.

As will be appreciated by those skilled in the art, the devicesillustrated in FIGS. 14-31 are can be configured to be deliverable intoa patient's lung and configured to reshape lung tissue while allowingfluid to flow both directions past the implant. A number of additionalfeatures described in related U.S. patent application Ser. No.12/558,206 entitled Enhanced Efficacy Lung Volume Reduction Devices,Methods, and Systems, such as lock features, decoupler systems,activation systems, and retrieval systems may be used with aspects ofthe present invention. The full disclosure of U.S. patent applicationSer. No. 12/558,206 is incorporated herein by reference.

FIGS. 32A-C illustrates the process of implanting the device within alung. As is evidence, the device 2810 is advanced is a configurationwhere the device adapts to the anatomy of the lungs through the airwaysand into, for example, the bronchioles until it reaches a desiredlocation relative to the damaged tissue 32. The device is then activatedby engaging the actuation device, causing the device to curve and pullthe lung tissue toward the activated device (see, FIG. 32B). The devicecontinues to be activated until the lung tissue is withdrawn a desiredamount, such as depicted in FIG. 32C. As will be appreciated by thoseskilled in the art, withdrawing the tissue can be achieved by, forexample, curving and compressing a target section of lung tissue upondeployment of one of the configurable devices disclosed herein. Onceactivated sufficiently, the deployment device is withdrawn from the lungcavity.

A variety of steps for performing a method according to the inventionwould be appreciated by those skilled in the art upon review of thisdisclosure. However, for purposes of illustration, FIG. 33A illustratesthe steps including, insertion of the device 3610, activating the device3620, such as by activating an actuator; bending the device into adesired configuration 3630 and locking the device into a deployedcondition. As will be appreciated the step of bending the device can beachieved by activating the actuator, as described above, or by theimplant being restored into a preconfigured shape.

In one embodiment, the device operation includes the step of inserting abronchoscope into a patient's lungs and then inserting anintra-bronchial device or lung volume reduction device into thebronchoscope. The intrabronchial device is then allowed to exit thedistal end of the bronchoscope where it is pushed into the airway. Avariety of methods can then be used to verify the positioning of thedevice to determine if the device is in the desired location. Suitablemethods of verification include, for example, visualization viavisualization equipment, such as fluoroscopy, CT scanning, etc.Thereafter the device is activated by pulling the pull wire proximally(i.e., toward the user and toward the exterior of the patient's body).At this point, another visual check can be made to determine whether thedevice has been positioned and deployed desirably. Thereafter, thedevice can be fully actuated and the ratchet can be allowed to lock andhold the device in place. Thereafter, the implant is decoupled from thedelivery catheter and the delivery catheter is removed.

Another method of tensioning the lung is shown in FIG. 33B whichillustrates steps that include, applying bending loads or force tostrain a device from a first shape into a deliverable shape withoutplastically or permanently bending the device 3640, delivering thedevice into the patient using the bronchoscope or other delivery systemcomponents to hold the device in a deliverable shape while it is beingintroduced 3650 and then removing the constraint used to hold the deviceto allow it to recover back to its first shape 3660. Elastic recovery ofthe device will drive the device to a more bent condition that willapply force to nearby lung tissue. The bending forces locally compresstissue near the implant and apply tension on lung tissue in surroundingregions to restore lung recoil and enhance breathing efficiency. Thefirst shape is adapted to be elastically constrained by a deliverydevice to a deliverable configuration whereby removal of the deliverydevice allows the implant to recoil and be reshaped closer to its firstshape.

FIG. 34 illustrates a system 4901 that may be used to deliver theimplant device. The many components of the system may be needed to guidethe bronchoscope 4902 to a site that is appropriate for implantdelivery. The airway guide wire has a distal floppy section 4913 thatcan be steered into any desired airway by rotating the slight curve atthe distal tip to the appropriate trajectory at airway bifurcations. Toapply torque to the wire, devices such as a locking proximal handle 4915may be attached to the proximal end of the wire 4912. The wire tip maybe blunt such as the ball tip shown 4914. In some embodiments, the wiremay be adapted and configured to pass through a dilator catheter 4909that is shaped to provide a smooth diameter transition from the wirediameter to the delivery catheter 4906 diameter. The distal tip of thedilator 4910 should be tapered 4911 as shown. The dilator prevents theopen end of the delivery catheter 4906 to dig into lung tissue in anunintended way. The dilator hub 4916 may be made as a Y-fitting to allowthe user to couple a syringe and inject radiopaque dye through thedilator lumen to increase the visibility of the airways, whichfacilitates the use of an x-ray guidance system, such as fluoroscopy orcomputed tomography. The delivery catheter may be used without the wireand dilator. The catheter 4906 is designed to constrain the device in adeliverable shape while it is advanced through the system and into thepatient. The distal end 4907 may be configured from a floppier polymeror braid than the proximal end 4906 and the distal tip may furtherinclude a radiopaque material associated with the tip, either integralor adjacent, to identify the position of the tip relative to otheranatomical locations, such as bones. Providing one or more radiopaquemarkers facilitates using x-ray guidance system to position the distalend of the device in situ relative to a target anatomy. The proximaltermination of the delivery catheter 4908 may further be adapted toincorporate a lockable hub to secure the loading cartridge 3801 with asmooth continuous lumen. The delivery catheter 4906 is shown introducedinto the bronchoscope side port 4905 and out the distal end of the scope4917. A camera 4903 is shown attached to the end of the scope with acable 4904, or other delivery mechanism, to transmit the image signal toa processor and monitor. The loading cartridge, delivery catheter,dilator, guide wire and wire nut may be made from any materialidentified in this specification or materials well known to be used forsimilar products used in the human vascular tract by radiologists.

FIG. 35 illustrates a delivery system 5001 that has been placed into ahuman lung. The bronchoscope 4902 is in an airway 5002. The scope camera4903 is coupled to a video processor 5004 via a cable 4904. The image isprocessed and sent through a cable 5005 to a monitor 5006. The monitorshows a typical visual orientation on the screen 5007 of a deliverycatheter image 5008 just ahead of the optical element in the scope. Thedistal end of the delivery catheter 4907 protrudes out of the scope inan airway 5002 where the user will place an implant device 3703. Theimplant 3703 is loaded into a loading cartridge 3801 that is coupled tothe proximal end of the delivery catheter via locking hub connection3802. A pusher grasper device 5009 is coupled to the proximal end of theimplant 3703 with a grasper coupler 5010 that is locked to the implantusing an actuation plunger 5012, handle 5011 and pull wire that runsthrough the central lumen in the pusher catheter. By releasably couplingthe pusher to the implant device and advancing pusher/grasper device5009, the user may advance the implant to a position in the lung in adeployed configuration. The user can survey the implant placementposition and still be able to retrieve the implant back into thedelivery catheter, with ease, if the delivery position is less thanideal. The device has not been delivered and the bottom surface of thelung 5003 is shown as generally flat and the airway is shown asgenerally straight. These may both be anatomically correct for a lungwith no implant devices. If the delivery position is correct, the usermay actuate the plunger 5012 to release the implant into the patient.

FIG. 36 illustrates generally the same system after the implant has beendeployed into the airway 5103. The implant 5102 and pusher 5101 has beenadvanced through the delivery catheter 4907 to a location distal to thescope 4902. The pusher grasping jaws 5010 are still locked onto theproximal end of the implant 5102 but the implant has recovered to apre-programmed shape that has also bent the airway 5103 into a foldedconfiguration. By folding the airway, the airway structure has beeneffectively shortened within the lung and lung tissue between portionsof the implant has been laterally compressed. Since the airways are wellanchored into the lung tissue, the airway provides tension on thesurrounding lung tissue which is graphically depicted by showing thepulled (curved inward) floor of the lung 5104. The image from the camera4903 is transmitted through the signal processor 5004 to the monitor5006 to show the distal tip of the delivery catheter 5101, distalgrasper of the pusher 5010 and proximal end of the implant 3703. Thegrasper may be used to locate, couple to and retrieve devices that havebeen released in the patient. The implant performs work on the airwaysand lung tissue without blocking the entire lumen of the airway. This isa benefit in that fluid or air may pass either way through the airwaypast the implant device.

FIG. 37 illustrates delivery system 5200 as placed into a patient body,and particularly into a human lung. Delivery system 5200 may begenerally similar to system 4901 or 5001 described above. The distal end5240 of bronchoscope 4902 extends into an airway system toward an airwayportion or axial region 5002, sometimes referred to as an axial segment.The scope camera 4903 is coupled to a video processor 5004 via a cable4904. The image is processed and sent through a cable 5005 to a monitor5006. Monitor 5006 shows on screen 5007 a portion of a delivery catheterimage 5008 just ahead of the optical image capture element in the scope.In some embodiments, the scope may be constrained by a relatively largecross-section to advancement only to a “near” region of the lungadjacent the major airways. Hence, the optical image has a viewfieldthat extends only a limited distance along the airway system, and itwill often be desirable to implant some, most, or all of the implantbeyond a field of view 5242 of scope 4902.

Guidewire 5203 is threaded through bronchoscope 4902 and through theairway system to (and through) airway 5002. As described above,guidewire 5203 may optionally have a cross-section significantly smallerthan that of the scope and/or the delivery catheter. Alternativeembodiments may use a relatively large diameter guidewire. For example,rather than relying on a tapering dilator between the guidewire and thedelivery catheter, the guidewire may instead be large enough to mostlyor substantially fill the lumen of the delivery catheter, while stillallowing sliding motion of the guidewire through the lumen. Suitableguidewires may have cross-section in a range from about 5 Fr to about 7Fr, ideally being about 5½ Fr, while the delivery catheter may bebetween about 5 Fr and 9 Fr, ideally being about 7 Fr. A distal end 5209of the guidewire 5203 may be angled as described above to facilitatesteering. Still further variations are also possible, including deliveryof the implant directly thru a working lumen of an endoscope (with useof a separate delivery catheter). In particular, where a cross-sectionalsize of a bronchoscope allows the scope to be advanced to a distal endof the target airway region, the bronchoscope itself may then be used asa delivery catheter, optionally without remote imaging.

A fluoroscopic system, an ultrasound imaging system, an MRI system, acomputed tomography (CT) system, or some other remote imaging modalityhaving a remote image capture device 5211 allows guidance of theguidewire so that the guidewire and/or delivery catheter 5201 can beadvanced beyond the viewing field of bronchoscope 4902. In someembodiments, the guidewire may be advanced under remote image guidancewithout the use of a scope. Regardless, the guidewire can generally beadvanced well beyond the near lung, with the distal end of the guidewireoften being advanced to and/or through the mid-lung, optionally towardor to the small airways of the far lung. When a relatively largeguidewire is used (typically being over 5 Fr., such as a 5½ Frguidewire), the cross-section of the guidewire may limit advancement toa region of the airway having a lumen size appropriate for receiving theimplants described above. The guidewire may have an atraumatic end, withexemplary embodiments having a guidewire structure which includes acorewire affixed to a surrounding coil with a resilient or low-columnstrength bumper extending from the coil, the bumper ideally formed byadditional loops of the coil with separation between adjacent loops soas to allow the bumper to flex axially and inhibit tissue damage. Arounded surface or ball at the distal end of the bumper also inhibitstissue injury. A distal end 5244 of laterally flexible delivery catheter5201 can then be advanced through the lumen within bronchoscope 4902 andover guidewire 5203 under guidance of the imaging system, ideally tillthe distal end of the delivery catheter is substantially aligned withthe distal end of the guidewire.

The distal portion of guidewire 5203 is provided with indicia of length5206, the indicia indicating distances along the guidewire from distalend 5209. The indicia may comprise scale numbers or simple scalemarkings, and distal end 5244 of catheter 5201 may have one or morecorresponding high contrast markers, with the indicia of the guidewireand the marker of the catheter typically visible using the remoteimaging system. Hence, remote imaging camera 5211 can identify, track orimage indicia 5206 and thus provide the length of the guidewire portionextending between (and the relative position of) the distal end of thebronchoscope and the distal end 5209 of guidewire 5203. Indicia oflength 5206 may, for example, comprise radiopaque or sonographic markersand the remote imaging modality may comprise, for example, an x-ray orfluoroscopic guidance system, a computed tomography (CT) system, an MRIsystem, or the like. Exemplary indicia comprise markers in the form ofbands of high-contrast metal crimped at regular axial intervals to thecorewire with the coil disposed over the bands, the metal typicallycomprising gold, platinum, tantalum, iridium, tungsten, and/or the like.Note that some of the indicia of the guidewire are schematically shownthrough the distal portion of the catheter in FIG. 37. Indicia of length5206 thus facilitate using a guidance system to measure a length ofairway 5002 or other portion of the airway system beyond the field ofview of the scope, thereby allowing an implant of appropriate length tobe selected.

Remote imaging modality 5221 is coupled to imaging processor 5224 viacable 5215. Imaging processor 5224 is coupled to a monitor 5226 whichdisplays an image 5228 on screen 5227. Image 5228 shows the indicia oflengths 5205 and 5206 of delivery catheter 5201 and guidewire 5203,respectively. As described above, when a small-diameter guidewire isused a dilator 5217 may be advanced through the lumen of the catheter sothat the distal end of the dilator extends from the distal end ofdelivery catheter 5201 when the catheter is being advanced. Dilator 5217atraumatically expands openings of the airway system as deliverycatheter 5201 advances distally. Dilator 5217 tapers radially outwardlyproximal of the distal tip of guidewire 5203, facilitating advancementof the catheter distally to or through the mid-lung toward the far lung.Once the catheter has been advanced to the distal end of airway portion5002 targeted for delivery (optionally being advanced over the guidewireto the distal end of the guidewire when a large diameter guidewire isused to identify a distal end of a target region for an implant, or asfar as the cross-section of the catheter allows the catheter to besafely extended over a smaller diameter guidewire), the length of theairway (optionally between the distal end of the guidewire and thedistal end of the bronchoscope) is measured. The dilator 5217 (if used)and guidewire 5203 are typically withdrawn proximally from delivercatheter 5201 so as to provide an open lumen of the delivery catheterfrom which a lung volume reduction device or implant can be deployed.

FIGS. 38A and 38B show an implant 5300 for treating airway 5002 of alung. As described above, airway 5002 comprises a portion of a branchingairway system, and the airway targeted for deployment will typicallydefine an airway axis 5340. Implant 5300 comprises an elongate body5301, a distal end 5303, and a proximal end 5305. Elongate body 5301 isbiased to bend to a bent deployed configuration as described above andas shown in FIG. 38B. A pusher grasper device 5009 is coupled to theproximal end 5305 with a grasper coupler 5010 that is locked to implant5300 using an actuation plunder 5012, handle 5011, and pull wire thatruns through the central lumen in the pusher catheter. Prior todeployment, implant 5300 may be loaded into a tubular loading cartridge,for example, cartridge 3801, and advanced from the loading cartridgeinto the lumen of catheter 5301. Pusher grasper device 5009 can advanceimplant 5300 through delivery catheter 5201. As shown in FIG. 38A, whenrestrained within delivery catheter 5201, elongate body 5301 ismaintained in a straightened configuration which defines a long axisbetween the distal end 5303 and proximal end 5305. As shown in FIG. 38B,when pusher grasper device 5009 axially restrains implant 5300 andcatheter 5201 is pulled proximally from airway axial region 5002,implant 5300 resiliently returns to a bent deployed configuration tobend the airway 5002. More specifically, the airway axis 5340 goes froma relatively straight configuration to a highly bent configuration, withlateral movement of the elongate body and surrounding airway structurethereby compressing adjacent tissue. Once catheter 5201 has beenwithdrawn from over elongate body 5301, the deployment can be evaluated.The user may axially restrain the implant 5300 while catheter 5201 isadvanced axially so as to recapture the implant if the deployment doesnot appear satisfactory, or the user may actuate plunger 5012 to releaseimplant 5300. Implant 5300 may be loaded into a tubular loadingcartridge, for example, cartridge 3801, and advanced from the loadingcartridge into the lumen of catheter 5301.

FIG. 39 shows a plurality of implants including implant 5300A, 5300B,and 5300C. Each of these implants may have different sizes, lengths, andshapes from each other. When using delivery system 5200, guidewire 5203may be advanced to a target region near the distal end of the airwaysystem. Guidewire 5203 may be advanced distally until further distaladvancement is limited by the distal end of the guidewire beingsufficiently engaged by the surrounding lumen of the airway system.Delivery catheter 5201 can then be advanced so that a distal end ofcatheter 5201 is adjacent a distal end of the guidewire. The distancealong the indicia of length 5205 from the bronchoscope to the distal endof guidewire 5203 may be used to select an implant having an elongatebody 5301 with a desired length. The desired length may be lesser,greater or about the same as the distance between the distal end ofdelivery catheter 5201 and distal end of the bronchoscope as indicatedby the indicia 5206. The elongate body 5301 having the selected lengthmay be advanced and deployed into the lung via the airway system andusing pusher grasper 5009 as described above. To provide a desirableimplant shelf life and/or a desirable deployment force for compressingtissues using self-deploying elongate bodies (including those usingresilient materials and/or using superelastic materials such as Nitinol™or the like), it may be advantageous to store the various implants ofvarious sizes in a relaxed state. Once the desired implant geometry orother characteristics have been identified, the selected implant 5300may be loaded into a loading cartridge 5401 (and subsequently into thelumen of delivery catheter 5201) using pusher grasper device 5009.Pusher grasper device 5009 may be tensioned proximally and/or loadingcartridge 5401 may be pushed distally so that elongate body 5301straightens axially. The loading cartridge 5401 and implant 5300 canthen be coupled to the other components of the delivery system, and theimplant advanced into the airway as described above.

In exemplary embodiments, the pusher grasper 5009 moves distally whilethe catheter 5201 is retracted proximally from over the implant duringdeployment. The selected implant may have a length greater than themeasured distance between the distal end of the guidewire (and hence theend of the delivery catheter) and the distal end of the scope. This canhelp accommodate recoil or movement of the ends of the implant towardeach during delivery so as to avoid imposing excessive axial loadsbetween the implant and tissue. Distal movement of the pusher grasper5009 and proximal end of the implant during deployment also helps keepthe proximal end of the implant within the field of view of thebronchoscope, and enhances the volume of tissue compressed by theimplant. Exemplary implants may be more than 10% longer than themeasured target airway axial region length, typically being from 10% toabout 30% longer, and ideally being about 20% longer. Suitable implantsmay, for example, have total arc lengths of 125, 150, 175, and 200 mm.

Related U.S. patent application Ser. No. 12/558,206 describes exemplarymethods for treating a patient and evaluating the treatment, each ofwhich may be used with aspects of the present invention. For example,the treatment method may comprise delivering an implant within the lungand then evaluating the patient's breathing thereafter to determinewhether more implants are needed. Alternatively, a plurality of implantsmay be delivered within the patient's lungs before an evaluation. Thepatient's lungs may be evaluated by measuring a forced expiratory volume(FEV) of the patient, measuring/visualizing a change in tissue densityat the implantation region, measuring/visualizing displacement of thediaphragm or of the lung fissures, etc.

In some embodiments, an implant is deployed in a straight configurationwith the use of a catheter, e.g., catheter 5201, to contain it in agenerally straight shape. Alternative embodiments may use the workinglumen of the bronchoscope directly so that the bronchoscope is used as adelivery catheter. Upon removal of the constraining catheter, theimplant recoils to a deployed shape that can be easily identified by thefact that the distance from one end to the second is reduced. Theproximal end of the implant may be grasped, e.g., with pusher grasperdevice 5009, and held so that the distal end of the implant remainsengaged against the desired airway tissue as the length of the implantis progressively unsheathed (by withdrawing the catheter proximally).High tensile forces might be generated between the distal portion of theimplant and the airway tissue if the proximal end of the implant is heldat a fixed location throughout deployment, as the implant is biased torecoil or bring the ends together when released. Hence, it can beadvantageous to allow the proximal end of the implant to advancedistally during release, rather than holding the implant from recoiling,as these forces may be deleterious. For example, the distance and tissuethickness between the distal end of the implant and the lung surface isshort, there may be little strain relief on the tissue and the risk ofrupture may be excessive. Additionally, the implant might otherwise tendto foreshortened after it is released by the grasper. Whenforeshortening occurs, the proximal end of the implant may traveldistally beyond the viewing field of the bronchoscope and the user canhave difficulty retrieving the implant reliably.

Thus, as schematically shown in FIGS. 40A-40C, an implant 5300 having alength longer than that of the target axial region 5505 may be selectedto be deployed in some cases. As described above, a guidewire may beadvanced distally from the bronchoscope until the guidewire advancementis inhibited by engagement with the surrounding airway, with theguidewire optionally being relatively large in cross-section (suchhaving a size of between about 5 F and 7 F, ideally having a size ofabout 5½ F). This allows the guidewire to be advanced to (but notexcessively beyond) a target site for the distal end of the implant(which may have an atraumatic ball surface with a diameter from about 1to about 3 mm, ideally being about 1.5 mm). As shown in FIG. 40A,catheter 5201 is advanced distally from the distal end of bronchoscope4902 over the guidewire until the distal end of catheter 5201 is alignedwith the distal end of the guidewire or till the distal end of thecatheter limits further distal advancement due to the distal end ofcatheter 5201 being similarly sufficiently engaged by the surroundinglumen of the airway system 5002. A length 5505 of the target axialregion of the airway is measured. Length 5505 may be the distancebetween the distal end of the advanced catheter 5201 and the distal endof the bronchoscope 4902, and the guidewire can be withdrawn proximallyafter the measurement. An implant 5300 having a length greater than themeasured length 5505 is selected and distally advanced through catheter5201 using pusher grasper 5009 as previously described. Implants havinga length of at least 10% more, preferably about 20% more, than themeasured target axial region may be selected.

FIG. 40B shows the deployment of implant 5300. Implant 5300 is advancedthrough the lumen of catheter 5201 to adjacent its distal end and thecatheter 5201, the distal end of the implant is (at least initially)held axially in place, and the catheter is withdrawn proximally fromover a distal portion of the implant. As catheter 5201 is withdrawn,implant 5300 bends laterally and compresses a portion of airway 5002. Asshown in FIG. 40B, a larger portion airway 5002 can be compressed byimplant 5300 once catheter 5201 is fully withdrawn such that it nolonger restrains implant 5300. As the catheter is progressivelywithdrawn, the proximal end of the implant moves distally relative tothe surrounding bronchoscope and airway tissue. The proximal end ofimplant 5300 may also be released by pusher grasper 5009 after implant5300 has foreshortened (when measured along the axial center of theairway) gradually throughout its release.

By using a longer implant 5300, the proximal end of implant 5300 canalso be fed into the airway while the potential energy of the implant isbeing freed to apply work on the lung tissue (while the catheter isbeing pulled off of the implant). The lung airways can be distorted sothe airway cross section is pushed to a more oval shape. Longer implantscan tend to zigzag back and forth across the airway lumen so thatimplants that are significantly longer than the measured airway lengthcan be introduced. For example, a 150 mm long (arc length) implant canbe deployed into a 100 mm long airway. The greater length of the implantmay minimize the uncontrolled recoil that may cause the proximal end tobe lost in the patient upon release. Greater implant length can alsoallow the user to feed the implant into the patient while the catheteris removed without over stressing the lung tissue. Additionally, shouldforeshortening of the longer implant occur, the proximal end of theimplant can still remain within the viewing field of the bronchoscopeand the user can thus retain the ability to retrieve the implantreliably. It should be understood that the length of the implantrelative to the diameter of the airway may be much greater than theschematic illustration of FIGS. 40A-40C, that the implant may have morecomplex three dimensional curvature to effect volumetric compression ofthe lung tissue, and the like.

As will be appreciated by those skilled in the art, the device can bemanufactured and deployed such that it is deliverable through abronchoscope. When actuated, the device can be adapted and configured tobend or curl which then distorts lung tissue with which the device comesin contact. Lung tissues that may be beneficially distorted by thedevice are airways, blood vessels, faces of tissue that have beendissected for introduction of the device or a combination of any ofthese. By compressing the lung tissue, the device can result in anincrease in elastic recoil and tension in the lung in at least somecases. Additionally, in some instances, lung function can be at leastpartially restored regardless of the amount of collateral ventilation.Further, the diaphragm may, in some instances, move up once greatertension is created which enables the lung cavity to operate moreeffectively.

Devices according to the invention have a small cross-section, typicallyless than 10 F. The flexibility of the device prior to deploymentfacilitates advancement of the device through the tortuous lung anatomy.Once deployed, the device can remain rigid to hold and maintain a tissuedeforming effect. Further, the device design facilitates recapture,de-activation and removal as well as adjustment in place.

Candidate materials for the devices and components described hereinwould be known by persons skilled in the art and include, for example,suitable biocompatible materials such as metals (e.g. stainless steel,shape memory alloys, such a nickel titanium alloy (nitinol), titanium,and cobalt) and engineering plastics (e.g. polycarbonate). See, forexample U.S. Pat. No. 5,190,546 to Jervis for Medical DevicesIncorporating SIM Memory Alloy Elements and 5,964,770 to Flomenblit forHigh Strength Medical Devices of Shape Memory Alloy. In someembodiments, other materials may be appropriate for some or all of thecomponents, such as biocompatible polymers, includingpolyetheretherketone (PEEK), polyarylamide, polyethylene, andpolysulphone.

Polymers and metals used to make the implant and delivery system may becoated with materials to prevent the formation and growth of granulartissue, scar tissue and mucus. Many of the drugs used with stentproducts to arrest hyperplasia of smooth muscle cells in blood vesselsafter deploying metallic stents will work very well for these devices.Slow release drug eluting polymers or solvents may be used to regulatethe release of drugs that include any substance capable of exerting atherapeutic or prophylactic effect for a patient. For example, the drugcould be designed to inhibit the activity of smooth muscle cells. It canbe directed at inhibiting abnormal or inappropriate migration and/orproliferation of smooth muscle cells to inhibit tissue mass buildup. Thedrug may include small molecule drugs, peptides or proteins. Examples ofdrugs include antiproliferative substances such as actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich ofMilwaukee, Wis., or COSMEGEN available from Merck). Synonyms ofactinomycin D include dactinomycin, actinomycin IV, actinomycini,actinomycin X₁, and actinomycin C₁. The active agent can also fall underthe genus of antineoplastic, anti-inflammatory, antiplatelet,anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic,antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co. of Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S. A. of Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn of Peapack N.J.), and mitomycin(e.g. Mutamycin® from Bristol-Myers Squibb). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein Hh/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc. of Cambridge, Mass.).Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. Capoten® and Capozide® from Bristol-Myers Squibb), cilazapril orHsinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc. ofWhitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co.), monoclonal antibodies (such as thosespecific for Platelet-Derived Growth Factor (PDGF) receptors),nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors,suramin, serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which jtnay be appropriate includealpha-interferon, genetically engineered epithelial cells, tacrolimus,dexamethasone, and rapamycin and structural derivatives or functionalanalogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by thetrade name of EVEROLIMUS available from Novartis of New York, N.Y.),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

Other polymers that may be suitable for use in some embodiments, forexample other grades of PEEK, such as 30% glass-filled or 30% carbonfilled, provided such materials are cleared for use in implantabledevices by the FDA, or other regulatory body. The use of glass filledPEEK would be desirable where there was a need to reduce the expansionrate and increase the flexural modulus of PEEK for the instrumentGlass-filled PEEK is known to be ideal for improved strength, stiffness,or stability while carbon filled PEEK is known to enhance thecompressive strength and stiffness of PEEK and lower its expansion rate.Still other suitable biocompatible thermoplastic or thermoplasticpolycondensate materials may be suitable, including materials that havegood memory, are flexible, and/or deflectable have very low moistureabsorption, and good wear and/or abrasion resistance, can be usedwithout departing from the scope of the invention. These includepolyetherketoneketone (PEKK), polyetherketone (PEK),polyetherketoneetherketoneketone (PEKEKK), andpolyetheretherketoneketone (PEEKK), and generally apolyaryletheretherketone. Further other polyketones can be used as wellas other thermoplastics. Reference to appropriate polymers that can beused in the tools or tool components can be made to the followingdocuments, all of which are incorporated herein by reference. Thesedocuments include: PCT Publication WO 02/02158 A1, to VictrexManufacturing Ltd. entitled Bio-Compatible Polymeric Materials; PCTPublication WO 02/00275 A1, to Victrex Manufacturing Ltd. entitledBio-Compatible Polymeric Materials; and PCT Publication WO 02/00270 A1,to Victrex Manufacturing Ltd. entitled Bio-Compatible PolymericMaterials. Still other materials such as Bionate®, polycarbonateurethane, available from the Polymer Technology Group, Berkeley, Calif.,may also be appropriate because of the good oxidative stability,biocompatibility, mechanical strength and abrasion resistance. Otherthermoplastic materials and other high molecular weight polymers can beused as well for portions of the instrument that are desired to beradiolucent.

Any implant described herein can be made of a metallic material or analloy such as, but not limited to, cobalt-chromium alloys (e.g.,ELGILOY), stainless steel (316L), “MP3 SN,” “MP2ON,” ELASTINITE(Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy,platinum, platinum-based alloys such as, e.g., platinum-iridium alloy,iridium, gold, magnesium, titanium, titanium-based alloys,zirconium-based alloys, or combinations thereof. Devices made frombioabsorbable or biostable polymers can also be used with theembodiments of the present invention. “MP35N” and “MP2ON” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co. of Tenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP2ON” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims presented will define the scope of the inventionand that methods and structures within the scope of these claims andtheir equivalents be covered thereby.

What is claimed is:
 1. A system for treating a patient presenting with agenetically associated chronic obstructive pulmonary disease, the systemcomprising: a self-recovering first coil implant, wherein the first coilimplant is configured to increase tension of a lung having alveolardamage caused by alpha-1 antitrypsin deficiency (AATD) and therebyimprove breathing function of the lung; and a delivery system configuredto deliver the first coil implant into an airway of the lung, whereinthe delivery system comprises a cartridge configured to retain the firstcoil implant in a straight configuration; wherein the first coil implantis configured to recover to a non-straight, pre-determined shape upondeployment within the airway the lung of the patient.
 2. The system ofclaim 1, wherein the delivery system further comprises: a catheterconfigured to function as a conduit to deliver the first coil implant toa targeted treatment area of the lung; a guidewire configured to guidethe catheter to the targeted treatment area; and forceps configured tocouple to a proximal portion of the first coil implant for controllingplacement and release of the first coil implant at the targetedtreatment area.
 3. The system of claim 2, wherein the proximal portioncomprises a straight, stand-off proximal tail to facilitate recaptureand positioning of the first coil implant.
 4. The system of claim 1,wherein the first coil implant is configured to compress AATD affectedtissue of the lung to allow for increased elastic recoil to other tissueof the lung.
 5. The system of claim 1, wherein the first coil implantcomprises passivated nitinol.
 6. The system of claim 1, wherein thefirst coil implant has a length within a range from 100 mm to 150 mm toallow for placement in a lower lobe of the lung for treatment ofpanacinar emphysema associated with AATD.
 7. The system of claim 1,further comprising a second coil implant, wherein the first coil implantis relatively weak so as to be adapted for implantation in a lower lobeof the lung and the second coil implant is relatively strong so as to beadapted for implantation in an upper lobe of the lung.
 8. The system ofclaim 1, wherein the first coil implant comprises a trailing proximalend, and wherein the trailing proximal end has a smaller diameter thanthe rest of the first coil implant.
 9. The system of claim 8, whereinthe trailing proximal end is the most proximal 10 mm of the first coilimplant.
 10. The system of claim 1, wherein the first coil implant has adistal end and a proximal end, and wherein the distal end terminateswith a distal smooth atraumatic ball and the proximal end terminateswith a proximal smooth atraumatic ball.
 11. The system of claim 1,wherein the first coil implant has a self-recovering geometry configuredto reside in an airway diameter with an inner diameter of about 2 mmdistally and about 6 mm proximally.
 12. The system of claim 1, whereinthe cartridge comprises a plastic cylinder with a Luer lock tip.
 13. Thesystem of claim 1, wherein the delivery system further comprisesforceps, wherein the forceps is coupleable with a proximal end of thefirst coil implant.
 14. The system of claim 1, further comprising agenetic diagnostic sample delivery system, wherein the geneticdiagnostic sample delivery system comprises a container for storing agenetic sample.
 15. The system of claim 14, further comprising a geneticdiagnostic system configured to: receive the genetic sample; diagnoseAATD based on the genetic sample; and provide an indication suitable forprompting use of the delivery system.
 16. A system for treating apatient presenting with a genetically associated chronic obstructivepulmonary disease, the system comprising: a self-recovering first coilimplant, wherein the first coil implant is configured to increasetension of a lung having alveolar damage caused by a genetic disorderand thereby improve breathing function of the lung; and a deliverysystem configured to deliver the first coil implant into an airway ofthe lung, wherein the delivery system comprises a cartridge configuredto retain the first coil implant in a straight configuration; whereinthe first coil implant is configured to recover to a non-straight,pre-determined shape upon deployment within the airway the lung of thepatient.
 17. The system of claim 16, wherein the delivery system furthercomprises: a catheter configured to function as a conduit to deliver thefirst coil implant to a targeted treatment area of the lung; a guidewireconfigured to guide the catheter to the targeted treatment area; andforceps configured to couple to a proximal portion of the first coilimplant for controlling placement and release of the first coil implantat the targeted treatment area.
 18. The system of claim 16, furthercomprising a second coil implant, wherein the first coil implant isrelatively weak so as to be adapted for implantation in a lower lobe ofthe lung and the second coil implant is relatively strong so as to beadapted for implantation in an upper lobe of the lung.
 19. The system ofclaim 16, wherein the first coil implant has a length within a rangefrom 100 mm to 150 mm to allow for placement in a lower lobe of the lungfor treatment of panacinar emphysema associated with AATD.
 20. Thesystem of claim 16, further comprising a genetic diagnostic sampledelivery system, wherein the genetic diagnostic sample delivery systemcomprises a container for storing a genetic sample.